Anticancer Drug Discovery from the Marine Environment

15 Pages·2012·0.48 MB·English

218 Recent Patents on Anti-Cancer Drug Discovery, 2012, 7, 218-232
Anticancer Drug Discovery from the Marine Environment

Candida Nastrucci1,(cid:1), Alfredo Cesario1,2 and Patrizia Russo1,*
1Laboratory of Systems Approaches and Non-Communicable Diseases, IRCCS "San Raffaele Pisana", 2Catholic
University, Rome, Italy
Received: August 11, 2011; Accepted: November 11, 2011; Revised: November 17, 2011
Abstract: Discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs de-
rived from the marine environment are continuously developing and increasing. One of the most promising area is cancer
therapy. Currently, there are two drugs approved by the Food and Drug Administration (FDA) and European Agency for
the Evaluation of Medicinal Products (EMA) in cancer treatment, namely Cytarabine (Cytosar-U1®) and Eribulin (E7389
or Halaven®). Trabectedin (ET-743 or Yondelis1®), approved by EMA, is completing key Phase III studies in the U.S. for
final approval. It was estimated that 118 marine natural products (MNPs) are currently in preclinical trials, 22 MNPs in
clinical trials and 3 MNPs on the market. The characteristics and selectivity profiles of new drugs for cancer therapy, as
well as drugs disclosed in related patent applications, will be the focus of this review, providing a brief and ready to use
reference.
Keywords: Anticancer therapy, clinical trials cancer, human diseases, marine drugs, mechanism of action, multitargets, patent.
INTRODUCTION reveal some peculiar mechanisms of action (e.g. Trabectin,
ET-743, Yondelis®). Moreover, because these compounds
"A man is never lost at sea” by "The old man and the
are discharged into the water and rapidly diluted, they are
sea" Ernest Hemingway 1952.
characterized by a great potency in preserving their efficacy.
Natural products (NP) have been the keystone of antican- All of these properties are attractive for their possible use as
cer pharmacology for the past 50 years of anticancer chemo- lead compounds in pharmacology. However, the process to
therapy. These compounds derive from natural sources, such find a drug suitable for clinical use is long and expensive. It
as plants, animals or micro-organisms. Although the term NP has been estimated by Adams and Brantner, in 2010, that for
truly refers to any naturally occurring substance, usually, it is a new patented molecular entity the cost is $1214 millions
restricted to small molecules < 3,000 Daltons, synonymous [2]. Although a controversial new study questioned this cost
of “secondary metabolites” and characterized by consider- [3], it is clear that the price to develop a new drug remains
able structural diversity. These molecules are not necessary extremely high.
to the growth and development of the producing organism;
Since 1984, the Harbor Branch Oceanographic Institution
but are important to organism’ survival, defending (e.g.
(HBOI) in Fort Pierce, FL, has collected ocean organisms for
against predators or prey organisms) or attracting (e.g. odor-
drug discovery and currently holds about 30,000 samples in
ant fragrances in plants attracting insects) other organisms.
storage, publishing the structures of over 200 compounds
These compounds are widespread in marine sessile eukary-
with biological activities [4], including discodermolide and
otic organisms, such as sponges and tunicates, lacking es-
the ecteinascidins (e.g. Trabectin, ET-743, Yondelis®).
cape or avoidance mechanisms. However, the presence of
Nowadays, the NCI-DTP's (National Cancer Institute-
biologically active secondary metabolites in marine bacteria
Developmental Therapeutic Program) Natural Products Re-
raises the question about their ecological functions [1]. Thus,
pository [5] houses 10,000 marine organisms collected from
the interest in marine NP relies in their biodiversity that, in
more than 25 countries. In the 2007, as an example, Phar-
turn, reflects the multitude of interactions between these or-
maMar produced 110 inventions (660 patents granted; 700
ganisms and their environment. These interactions produce
on prosecution) covering potential anticancer agents from
the diverse complex chemical compounds observed, which
the sea [6]. However, only two compounds are licensed by

the Food and Drug Administration (FDA) and European
*Address correspondence to these authors at the IRCCS "San Raffaele Pisa- Agency for the Evaluation of Medicinal Products (EMA)-for
na", Via di Val Cannuta, 247-249, 00166 Rome, Italy; Tel: [phone] clinical use as an anticancer agent, namely cytarabine (Cyto-
3776; Fax: [phone]; 5668; E-mail: *[email protected]; sar-U1) and Eribulin (Halaven®), whereas Trabectin, (ET-
[email protected] 743 or Yondelis1®), that is approved by EMA, is completing
(cid:1)Note: The Author states to disagree with the use of animals and animal
key Phase III studies in the U.S. needed for approval [7-9].
models in research. As an author she is only responsible for the inclusion of
the in vitro research and human studies reported in this review. She is a Other compounds are underongoing Phase I and II clinical
“conscientious objector”, according to the Italian Law: "Legge n. 413 del 12 trial. However, different compounds, for example Sobli-
ottobre 1993" entitled “Norme sull'obiezione di coscienza alla sperimentaz- dotin® (Auristatin PE, TZT 1027; 10) and Tasidotin (Syn-
ione animale" (Italian Law on “conscientious objection to animal experi- thadotin®, ILX-651; 11) showed no activity or adverse side
ments”).
effects (see Table 1 reporting some examples) and were
(cid:21)(cid:21)(cid:20)(cid:21)-(cid:22)9(cid:26)(cid:19)/12 $100.00+.00 © 2012 Bentham Science Publishers
Anticancer Drug from Sea Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 219
Table 1. Marine-derived Drugs in Clinical Trials.
Compound Chemical Class Organism Mode of Action Company Status
Name
Cytarabine, Nucleoside with a modi- Sponge: Cryptotethia DNA Polymerase Bedford, Enzon, FDA-EMA Approved
ARA-C fied sugar crypta Inhibitor Pfizer for childhood ALL.
FDA-approved intrate-
cal in relapsed pediatric
leukemia7,8,9,12
Trabectedin Tetrahydroisoquinoline Tunicate: Ecteinascidia Binding to minor PharmaMar EMA Approved
alkaloid groove DNA alkilating
(ET-743), Yon- turbinate FDA: Orphan drug
delis® Guanine at N2. status for soft-tissue
sarcoma and ovarian
7,8,9
cancer
Eribulin Mesy- Fully synthetic macrocyc- Sponge: Halichondria Microtubule interfer- Eisai Inc. FDA-EMA
late (E7389), lic ketone, Halichondrin okaday, ing agent Approved for metastatic
Halaven® B analogue Axinella carteri (Hali- breast cancer7,8,9
chondrin B)
Neovastat® Aminosteroid Shark Calcium binding pro- Genaera Phase III
tein antagonist
(AE-941) Negative in unresectable
stage II NSCLC13
Soblidotin®*, Synthetic dolastatin 10 Opisthobranchs: Dola- Microtubule interfer- Daiichi Pharmaceutical Phase I -II 10
Auristatin PE, derivative peptide bella auricularia, ing and (Licensee)
(NSC-654663,
Marine cyanobacte- vascular disrupting
TZT-1027) rium: Symploca sp. agent
Kahalalide-F Cyclic depsipeptide Mollusc (marine slug): Lysosomotropic PharmaMar Phase II in NSCLC,
melanoma, liver carci-
Elysia rufescens
noma 14, 15
Plitidepsin, Cyclic depsipeptide Tunicate: Apoptosis inducer PharmaMar Phase II with some
Aplidin® Aplidium albicans limited clinical
activity 16
Bryostatin-1 Polyketide Bacterium/ Bryozoa: PKC(cid:1) activation National Cancer Phase II in colon-rectal
Bugala neritina cancer disease progres-
Institute
sion17. Phase II in com-

bination in different
cancers 95-96-97
Marizomib, (cid:2)-Lactam-(cid:1)-lactone bicy- Marine bacterium: 20S Proteasome in- Nereus Pharmaceuti- Phase II ongoing in
Salinosporami- cle Salinispora tropica hibitor cals NSCLC18
de A
(PI-0052)
Zalypsis®, Synthetic alkaloid tetra- Nudibranch: Double strand DNA PharmaMar Phase II unresectable
(PM00104) hydroisoquinoline breaks triggering a metastatic Ewing family
Jorunna funebris
DNA damage response of tumors (EFT)19
related to Jorumycin (Jorumycin)
Elisidepsin , Synthetic cyclic depsipep- Mollusc: Necrosis and plasma PharmaMar Phase IB/II In pretreated
tide of the kahalalides advanced gastroe-
(PM02734), Elysia rufescens membrane alterations
Irvalec® family. Dehydro amino- sophageal cancer20
butyric acid-containing
peptides
Tasidotin*, Third- generation Dolas- Mollusc: Microtubule interfer- Genzyme Phase I completed11
Synthadotin® tatin-15 analogue. Seven- ing agent
Aplysidae Corporation
subunit depsipeptide
(ILX-651)
220 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Nastrucci et al.
(Table 1) Contd….

Compound Chemical Class Organism Mode of Action Company Status
Name
LAF389 Bengamide B synthetic Sponge: Methionine aminopep- Novartis Phase I advanced
analogue. Amino acid tidase cancer21
Choristida (Ben-
derivative
gamide) inhibitor
Hemiasterlin Tripeptide Sponge: Microtubule interfer- Eisai Inc. Phase I22
(E7974) Siphonochalina ing agent
Taltobulin Hemiasterlins analogue. Sponge: Microtubule interfer- Wyeth Phase I23
(HTI-286) Tripeptide Siphonochalina (Hemi- ing agent (depolariz-
asterlins) ing)

Discodermolide Polyhydroxylated lactone Sponge: Discodermia Microtubule stabilizing Novartis Pharma AG Phase I24
dissoluta agent.
Spisulosine Sphingoid -type base Mollusc: RhoA as target PharmaMar Phase I25
(ES-285) Spisula polynyma
*Clinical trials with Soblidotin® (TZT 1027) and Tasidotin® (ILX-651) have been discontinued [26].

discontinued. Nonetheless, laboratory synthesis of modified
parent structure resulted in less severe toxicity and more (cid:2)(cid:3)(cid:4) (cid:2)(cid:3)(cid:4)

active compounds (see Table 1). Table 1 reports the names (cid:2) (cid:2)
of the original compounds with the producers, the chemical (cid:2) (cid:5) (cid:5) (cid:2)
class they belong to, the organisms where the drug was (cid:3)(cid:5)(cid:6)(cid:3)(cid:4) (cid:5) (cid:3)(cid:5)
(cid:5)
originally isolated and the principal mechanism of action (cid:3)(cid:5) (cid:5)(cid:3) (cid:7)
accompanied by their clinical status [7-26].
(cid:5)(cid:3) (cid:7)
Because the ecological “raison d'être” of these com- (cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:5)(cid:7)(cid:8)(cid:9)(cid:10) (cid:11)(cid:6)(cid:5)(cid:12)(cid:2)(cid:13)(cid:5)(cid:9)(cid:5)(cid:14)(cid:15)(cid:16)(cid:17)(cid:10)(cid:18)(cid:19)(cid:10)(cid:20)(cid:21)(cid:8)(cid:4)(cid:5)(cid:7)(cid:8)(cid:9)(cid:10)
pounds is defense [1], they are characterized by different
chemical structures Fig. (1-4) and different mechanisms of (cid:3)(cid:5)
action. Some of these compounds (see Table 1) belong to the (cid:3)(cid:4)(cid:2) (cid:3)(cid:5) (cid:5)
group of natural Microtubule-Targeting Agents (MTAs), (cid:5) (cid:5) (cid:5) (cid:2)(cid:3)(cid:3)(cid:5) (cid:5) (cid:5) (cid:5) (cid:5) (cid:5)(cid:3)
(cid:3) (cid:3)
while others show very peculiar and unique mechanisms of (cid:5)
(cid:5) (cid:5) (cid:8) (cid:5)(cid:5)
action. (cid:5)
(cid:2) (cid:5)

(cid:2)
Microtubule-Targeting Agents (MTAs) (cid:5)
(cid:5) (cid:5)(cid:3)
In eukaryotic cells microtubules (MTs), cytoskeletal hol-
(cid:25)(cid:6)(cid:5)(cid:7)(cid:10)(cid:21)(cid:4)(cid:10)(cid:26)(cid:8)(cid:9) (cid:22)(cid:6)(cid:8)(cid:7)(cid:17)(cid:14)(cid:8)(cid:9)(cid:13)(cid:23)(cid:10)(cid:24)(cid:3)(cid:14)(cid:5)(cid:4)(cid:10)
low fibers resulting from the interaction of (cid:1)/(cid:2) tubulin poly-
mers with microtubule-associated proteins (MAPs), play
numerous key roles important in cell proliferation, traffick- (cid:27)(cid:28)(cid:11)(cid:12)(cid:22)(cid:23)(cid:11)(cid:13)(cid:5)(cid:29)(cid:29)(cid:6)(cid:15)(cid:30)(cid:5)(cid:14)

ing, signaling and migration [27, 28]. Consequently, differ-
ent microtubule-binding agents (MTAs) have been devel- Fig. (1). Chemical Formula of marine-derivative drugs approved by
FDA-EMA.
oped as anticancer agents. MTAs at high concentrations
Cytarabine was obtained by:
change microtubule dynamics and induce cell death by stabi-
< A href =
lizing MTs, as Taxanes, or destabilizing them, like Vinca
http://science.jrank.org/pages/28147/cytarabine.html>cytarabine -
alkaloids. MTAs may also induce cell death at concentra-
abbr., ara</a>
tions disrupting microtubule dynamics that do not affect mi-
Gemcitabine: http://www.scbt.com/datasheet-209742-3-epi-
crotubule polymerization. Drugs bind to tubulin at specific
gemcitabine-gemcitabine-impurity.html
binding sites [27, 28]. Natural MTAs, such as paclitaxel,
Trabectidin: http://pt.wikipedia.org/wiki/ficheiro:trabectedin.png
vinblastine, or vincristine have been used in the clinic for Eribulin mesylate: http://en.wikipedia.org/wiki/file:eribulin.svg
years [27, 28]. However, drug-resistance, both inherent and
acquired is common [29]. Resistance is related to different ii). Direct alteration in the drug target through mutation [31]
mechanisms, such as: or polymorphisms in (cid:1)-tubulin isotypes [32].
i). Decreased cellular drug accumulation involving the iii). Expression of different (cid:2)-tubulin isotypes, overexpres-
ATP-binding cassette transporter (ABC-transporter) P- sion or aberrant expression of (cid:2)III-tubulin [33, 34].
glycoprotein (P-gp) efflux pump (product of the

multidrug resistance gene (MDR1) [30].
Anticancer Drug from Sea Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 221
(cid:6)(cid:3)(cid:9)
(cid:3)(cid:9)(cid:6)(cid:5) (cid:5)(cid:2) (cid:3) (cid:5)(cid:3)(cid:6)(cid:2)(cid:9)(cid:6)(cid:3)(cid:9)(cid:3)(cid:5)(cid:6)(cid:3)(cid:3)(cid:9)(cid:3)(cid:6)(cid:2)(cid:3)(cid:3)(cid:9)(cid:9)(cid:6)(cid:3)(cid:3)(cid:3)(cid:5)(cid:2) (cid:3)(cid:5)(cid:5)(cid:3)(cid:6)(cid:3)(cid:3)(cid:9) (cid:5) (cid:5)(cid:5)(cid:3)(cid:3)(cid:9)(cid:2)(cid:6) (cid:3)(cid:3)(cid:6)(cid:5)(cid:6)(cid:3)(cid:3)(cid:9)(cid:9) (cid:6)(cid:3)(cid:6)(cid:9)(cid:3)(cid:9)(cid:2) (cid:3)(cid:5)(cid:2)(cid:3) (cid:3)(cid:5)(cid:6)(cid:2)(cid:3)(cid:9) (cid:5)(cid:6)(cid:3)(cid:9)(cid:5)(cid:3)(cid:6)(cid:2)(cid:3)(cid:9)(cid:11) (cid:5) (cid:2)(cid:3) (cid:5) (cid:5)(cid:6)(cid:3)(cid:9)
(cid:2) (cid:5)
(cid:5)
(cid:3) (cid:2) (cid:3) (cid:6)(cid:3)(cid:9)
(cid:5) (cid:3)(cid:9)(cid:6)
(cid:3) (cid:11)(cid:17)(cid:6)(cid:8)(cid:24)(cid:4)(cid:5)(cid:4)(cid:8)(cid:9)(cid:13)(cid:31)(cid:22)
(cid:31)(cid:14)(cid:8)(cid:4)(cid:8)(cid:26)(cid:10)(cid:29)(cid:24)(cid:8)(cid:9) (cid:3)(cid:9)(cid:6)(cid:5)
(cid:11) (cid:2)(cid:3)
(cid:3)(cid:9)(cid:6)(cid:5) (cid:5) (cid:5) (cid:3)(cid:5)(cid:9)(cid:6)(cid:5)(cid:3)(cid:6)(cid:5)(cid:3)(cid:3)(cid:9)(cid:5)(cid:5) (cid:6)(cid:3)(cid:9) (cid:6)(cid:3)(cid:15)(cid:24)(cid:4)(cid:5)(cid:4)(cid:8)(cid:9)(cid:12)! (cid:11)(cid:2)(cid:3) (cid:11)(cid:3)(cid:2) (cid:11)(cid:2)(cid:3) (cid:3)(cid:11)(cid:4)(cid:2)(cid:3)(cid:2) (cid:3)(cid:2)(cid:2) (cid:11)(cid:2)(cid:3) (cid:11)(cid:11)(cid:3)(cid:2) (cid:2)(cid:3)(cid:11)(cid:3)(cid:2)(cid:11)(cid:11)(cid:3)(cid:3)(cid:2)(cid:2) (cid:11)
(cid:5) (cid:5)(cid:3) (cid:11) (cid:11)
(cid:3)(cid:9)(cid:6) (cid:5) (cid:5)
(cid:3)(cid:9)(cid:6) ’(cid:5)%(cid:5)(cid:14)(cid:5)(cid:14)(cid:8)(cid:26)(cid:10)(cid:12)(cid:27)
(cid:5)(cid:3)
(cid:5) (cid:3)(cid:5) (cid:6)(cid:3)(cid:9)
(cid:3)(cid:9)(cid:6) (cid:5) (cid:5)(cid:6)(cid:3)(cid:9)
(cid:5) (cid:5) (cid:3) (cid:5) (cid:3) (cid:5) (cid:3) (cid:5) (cid:3)
(cid:5) (cid:2) (cid:2) (cid:2) (cid:2)
(cid:3)(cid:5) (cid:2) (cid:2) (cid:2)
(cid:5) (cid:3) (cid:5) (cid:3) (cid:5) (cid:5)
(cid:5) (cid:3) (cid:5) (cid:5) (cid:3) (cid:3) (cid:2) (cid:5) (cid:2)(cid:3) (cid:2)(cid:3)(cid:4) (cid:5) (cid:5) (cid:3)(cid:2)(cid:3)(cid:2)
(cid:2)(cid:3) (cid:2) (cid:3)(cid:2) (cid:5)(cid:5)(cid:3) (cid:3)(cid:2) (cid:5)
(cid:5)(cid:3) (cid:5) (cid:3) (cid:5) (cid:5)
(cid:5) (cid:5)(cid:3) (cid:2)(cid:3)
(cid:5) (cid:5) (cid:2)(cid:3) (cid:5) (cid:7)(cid:9)(cid:6) (cid:5)(cid:3)
(cid:6)(cid:10)
(cid:5) (cid:6)(cid:7)(cid:9)
"(cid:5)(cid:14)(cid:8)(cid:9)(cid:15)(cid:24)(cid:29)(cid:15)(cid:6)(cid:5)(cid:20)(cid:8)(cid:26)(cid:10)(cid:13)(cid:11) (cid:22)(cid:14)(cid:8)(cid:24)(cid:8)(cid:26)(cid:10)(cid:29)(cid:24)(cid:8)(cid:9)
(cid:31)(cid:23)##!#$
(cid:31)%(cid:5)(cid:24)(cid:10)(cid:13)&&(cid:13)(cid:24)(cid:4)(cid:17)(cid:26)(cid:3)
Fig. (2). Chemical Formula of marine-derivative drugs in Phase II clinical trials.
Auristatin-PE: http://www.chemicalbook.com/ChemicalProductProperty_EN_CB81253823.htm
Kahalide-F: http://www.medkoo.com/Anticancer-trials/Kahalalide-F.htm
Elisidepsin: http://www.medkoo.com/Anticancer-trials/Elisidepsin.htm
Plitidepsin: http://www.toxicology.cz/modules.php?name=News&file=article&sid=166
Bryostatin-1:
http://www.sigmaaldrich.com/catalog/ProductDetail.do?D7=0&N5=SEARCH_CONCAT_PNO%7CBRAND_KEY&N4=B7431%7CSIGM
A&N25=0&QS=ON&F=SPEC
Salinosporamide-A: http://pubs.acs.org/cen/news/85/i51/8551news1.html
PM00104: http://www.medkoo.com/Anticancer-trials/PM00104.htm
Soblitodin http://chemmol.com/chemmol/49400455.html
Elisidepsin http://www.medkoo.com/Anticancer-trials/Elisidepsin.htm

iv). Changes to the microtubules induced by interactions dolastatin, halichondrin, spongistatin, milnamide, hemiaster-
with or regulation by other cytoskeletal proteins, such as lin, dictyostatin, discodermolide, laulimalide, peloruside A,
(cid:1)-tubulin or actin-regulating proteins, that can affect the and zampanolide, some of which are now in development
ability of TBAs to induce mitotic arrest and cell death and others in clinical trials, as detailed in Table 1. The unic-
[35, 36]. ity of MTAs among anticancer drugs relies both on their
original mechanisms of action and on their extreme struc-
v). Expression of microtubule-associated proteins [37] and
tural diversity. Often natural potent antitumor MTAs were
stathmin [38].
the "lead compound" to more potent synthetic analogues,
vi). Defects in apoptotic pathways [39]. such as Eribulin mesylate (E7389, Halaven®, Eisai Europe,
Ltd.), a structurally simplified, synthetic analogue of Hali-
New MTAs derived from marine sources, such as soft
chondrin B Fig. (1). Eribulin binds at or in the vicinity of the
corals (eleutherobin and sarcodictyin) [40, 41] or sponges.
vinca domain, a region situated at the interface of two tubu-
Marine sponges, however, remain the most prolific source of
lin heterodimers, when these ones are arranged end-to-end
MTAs [42-44] and include different drug such as: jaspolide,
222 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Nastrucci et al.
(cid:5) (cid:5) Discodermolide:
(cid:2) http://en.wikipedia.org/wiki/File:Discodermolide_Structure.png
(cid:3)(cid:2) (cid:5)(cid:3) Spisulosine: http://www.marinebiotech.org/spisulosine.html
(cid:3)(cid:2) (cid:5)
(cid:2)
and overlies the exchangeable GTP site on (cid:2)-tubulin [45].

Eribulin mesylate is characterized by a unique mode of inter-
((cid:10)(cid:20)(cid:8)(cid:5)(cid:24)(cid:4)(cid:10)(cid:6)(cid:14)(cid:8)(cid:9)
action with tubulin inhibiting microtubule growth with no
effect on shortening events in association with sequestration

(cid:5) of tubulin into unusual aggregates [46]. Thus, the Eribulin
(cid:2) (cid:5)(cid:3) suppression of microtubule growth and dynamicity may be
(cid:5) (cid:2)(cid:3) (cid:5) enough to create abnormal spindle morphology suppressing

the transition from metaphase to anaphase without inducing
(cid:3)(cid:2) (cid:25)(cid:5)(cid:14)(cid:4)(cid:15)(cid:7)(cid:17)(cid:14)(cid:8)(cid:9) a stabilizing effect on microtubule ends. Although Eribulin is
a substrate for PgP it retains full in vitro activity in taxanes-

resistant cells, which have (cid:2)-tubulin mutations, suggesting
that Eribulin activity is not influenced by (cid:2)-tubulin muta-
(cid:5)(cid:3) (cid:5)(cid:6)(cid:3) (cid:5) tions [47].
(cid:9)(cid:3)
(cid:2) (cid:2)(cid:3)
ILX651 (Synthadotin® or Tasidotin®, Genzyme Corp.,

(cid:5)(cid:3) (cid:5)(cid:3) (cid:5) San Antonio, TX), an orally active synthetic third-generation
(cid:5) microtubule-targeted derivative of dolastatin-15 Fig. (3), and
(cid:5) its major metabolite tasidotin C-carboxylate may not act by
)(cid:11)(cid:27)*+, binding at the plus ends but by binding along the length of
the microtubules, working as taxol [48]. These observations
suggest that the principal mechanism of action of tasidotin is
(cid:3)(cid:5) the suppression of spindle microtubule dynamics [49].

(cid:5) (cid:5) (cid:5)(cid:3) (cid:5) (cid:2)(cid:3)(cid:4) (+)-Discodermolide (DDM) Fig. (3), a potent microtu-
bule stabilizer that binds with high affinity to the taxol site
(cid:5)(cid:3) (cid:5)
on (cid:2)-tubulin [50] shows higher tubulin polymerization po-
(cid:5)(cid:3) tency than Taxol forming shorter microtubules. DDM is a
(cid:28)(cid:8)(cid:24)(cid:21)(cid:15)(cid:26)(cid:10)(cid:6)(cid:20)(cid:15)(cid:14)(cid:8)(cid:26)(cid:10)
poor P-gp substrate and its activity is not influenced by mu-
tant (cid:2)-tubulin [51]. Unlike to Taxol, DDM induces acceler-

ated cell senescence [52].
(cid:5)(cid:3)
TZT-1027 Fig. (4) is a mitotic spindle poison interacting
with tubulin at the Vinca binding site [53] characterized by
(cid:2)(cid:3)(cid:12)(cid:16)(cid:6)(cid:14)(cid:15) an antitumor activity different from that of Vinca alkaloids
"(cid:29)(cid:8)(cid:24)(cid:17)(cid:14)(cid:15)(cid:24)(cid:8)(cid:9)(cid:10) (cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:9) (cid:9) [54]. In microarray experiments TZT-1027-induced gene

profiles different from those induced by classical antimicro-
tubule agents such as taxanes and Vinca alkaloids suggesting

that TZT-1027 has a different mechanism of action [55].
Disrupting the microtubule cytoskeleton of vascular endothe-
(cid:5)
(cid:3) (cid:3) lial cells TZT-1027 has antivascular activity on newly
(cid:2) (cid:5) (cid:2)
(cid:2) (cid:2) (cid:2) formed tumor vasculature [56]. TZT-1027 has an antiangio-
(cid:5) (cid:2) (cid:5) genic activity [57]. It was suggested that the antiangiogenic
(cid:5) activity would depend on the antivascular activity of TZT-
(cid:3)(cid:6)(cid:10) 1027 that induces morphologic changes causing the inhibi-
(cid:25)(cid:5)(cid:24)(cid:8)(cid:26)(cid:15)(cid:4)(cid:8)(cid:9)
tion of vascular endothelial cells proliferation [57].
Marine-derivatives in preclinical studies, such as Peloru-

side A Fig. (4), originally isolated from the marine sponge
Mycale hentscheli [58] and laulimalide Fig. (4) from the ma-
(cid:31)%(cid:5)(cid:24)(cid:10)(cid:13)&(cid:13)(cid:24)(cid:4)(cid:17)(cid:26)(cid:3)
rine sponge Cacospongia mycofijiensis [59] are two com-
pounds with some unique mechanisms of action that may
Fig. (3). Chemical Formula of marine-derivative drugs in Phase I
offer the foundation for a new generation of therapeutics
clinical trials.
with the same characteristics. Thus, it was proposed that
Tasidotin hydrochloride:
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB9 Peloruside A binds within a pocket on the exterior of (cid:2)-
2128761.htm tubulin at a previously unknown ligand site, rather than on
Hemiasterlin: (cid:1)-tubulin as suggested in earlier studies [60]. The lauli-
http://home.ncifcrf.gov/mtdp/Catalog/compounds/695242.html malide site is unique in its exposure to the outside surface of
Taltobulin: http://www.chemblink.com/products/228266-40-8.htm the microtubule [61].
LAF389: https://www.thieme-

connect.com/ejournals/abstract/synlett/doi/10.1055/s-0030-1259015
Anticancer Drug from Sea Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 223
(cid:5) logue of deoxy-cytidine (presence of a hydroxyl group in the
(cid:2)
(cid:2) (cid:5) (cid:5) (cid:1)-configuration at the 2(cid:1)-position of the sugar moiety) [62].
(cid:3) (cid:5) (cid:3) Among Ara-C analogues Gemcitabine (2', 2'-difluoro 2'-
(cid:5) (cid:2) (cid:2) (cid:5) (cid:3)(cid:2) deoxycytidine, dFdC) Fig. (1) is one of the most important
agents in the treatment of non-small cell lung cancer

(NSCLC) [63]. Although structurally similar to Ara-C, Gem-
(cid:25).(cid:25)(cid:12)!#/0 citabine shows distinctive mechanisms of action relating to
its mode of incorporation into the DNA and relating to the

(cid:5) (cid:5)(cid:3) presence of additional sites of action.

(cid:5)
(cid:3)(cid:5) (cid:5)(cid:3) Covalent Interaction with the Minor Groove of the DNA
(cid:3)(cid:5) (cid:5) Double Helix
(cid:3)(cid:5)
(cid:17)(cid:18)(cid:5) (cid:5)(cid:17)(cid:18) Ecteinascidin-743 (ET-743, Trabectedin or Yondelis®;
(cid:5)(cid:3) PharmaMar, Madrid, Spain) Fig. (1) exerts its antitumour
activity through covalent interaction with the minor groove
(cid:31)(cid:10)(cid:14)(cid:15)(cid:6)(cid:17)(cid:24)(cid:8)(cid:26)(cid:10)(cid:12)(cid:11) of the DNA double helix [64]. ET-743 is selective for GC-

rich sequences and forms an adduct with duplex DNA,
(cid:3) which is reversible upon denaturation [65] and induces a
(cid:5)
(cid:3)(cid:5) (cid:3)(cid:5) bend in the DNA helix directed towards the major groove
(cid:3)(cid:5)(cid:3)
(cid:3) (cid:5) (cid:5) (cid:2)(cid:3) (cid:3)(cid:2)(cid:5) (cid:2) [ti6o6n] a[6n7d, c6au8s];i ntgr:a ndsircercipt tiinotne-rcfoeruepnlcede wniutchl eaocttiidvea teedx ctrisainosnc rirpe--
(cid:5) (cid:5) (cid:5) (cid:2) (cid:6)(cid:10) pair (TCR) complex poisoning [69]; promotion of RNA po-
(cid:3) (cid:3) (cid:5) lymerase II degradation [70]; and DNA double-strand breaks
(cid:5) (cid:6)(cid:10)
generation [71]. Briefly, the modification of DNA conforma-
(cid:5) (cid:2)(cid:3) (cid:2)(cid:3) tion in turn determines the inhibition of activated transcrip-
)(cid:5)(cid:17)(cid:14)(cid:8)(cid:20)(cid:5)(cid:14)(cid:8)(cid:26)(cid:10) tion, whilst constitutive transcription appears unaffected
(cid:28)(cid:8)(cid:5)-(cid:15)(cid:9)(cid:5)(cid:20)(cid:8)(cid:26)(cid:10)
[67].

(cid:31)(cid:6)(cid:10)(cid:12)(cid:21)(cid:14)(cid:8)(cid:9)(cid:8)(cid:21)(cid:5)(cid:14) Cell Lysosomes

Kahalalide F (KF) Fig. (2) induces lysosomal membrane
Fig. (4). Chemical Formula of marine-derivative drugs in pre-
clinical studies. depolarization and consequently membrane disorders [72,
TZT-1027: 73]. Indeed, cell swelling and fatty acid accumulation was
http://www.chemicalbook.com/ChemicalProductProperty_EN_CB8 observed in KF-treated human breast cancer cell line MCF7
1253823.htm [72]. The same Authors suggested that in KF-treated cells
Peloruside: http://www4.utsouthwestern.edu/jdebralab/research.htm fatty acids may be released from membranes in phagosomes
Diazonamide A: through the activity of lysosomal lipases [72]. In the same
http://www.chemspider.com/blog/more-comments-about- study, membrane disorders were linked to other biochemical
diazonamide-a-other-efforts-to-distinguish-whats-real.html alterations including decrease in N-acetylaspartate, a precur-
Laulimalide: http://www- sor for membrane lipid synthesis through the supply of ace-
jmg.ch.cam.ac.uk/data/molecules/polyketides/laulimalide.html
tyl-CoA [72]. It was found that the cell membrane and in

particular, the 2-hydroxy fatty acid-containing ceramides are
All of these properties make marine derivative MTAs
important for PM02734, a synthetic cyclic depsipeptide re-
more promising agents than the classical MTAs.
lated to KF activity [74]. Consequently, it was proposed that
these results may have important implications in the devel-
DNA POLYMERASE INHIBITORS
opment of PM02734 therapy, because tumor cells with high
DNA polymerases are enzymes that catalyze DNA syn- levels of sphingolipid fatty acid 2-hydroxylation are ex-
thesis by forming a phosphodiester bond between the 5´- pected to be highly sensitive to this drug [74]. Interestingly,
phosphate of one deoxyribonucleotide and the 3´-hydroxyl of KF-induced cytotoxicity does not require gene expression or
another. They add deoxynucleotides, one at a time, to the 3´- caspase activity and does not cause cell cycle arrest or DNA
hydroxyl terminus of a preexisting DNA strand (a primer). degradation to induce death in human prostate and breast
As DNA polymerases are among the most attractive drug cancer cells [75]. In addition, mitochondria of KF-treated
targets, inhibitors of DNA polymerases are valuable tools in cells were severely damaged, showing increased matrix den-
both clinical and research settings. The knowledge of their sity, swelling of the cristae and wrapping by a single rough
structures and their modes of action give the basis for de- ER cistern and suggesting autophagy [75]. These features are
signing new drugs. Among these drugs the most important typical of “oncosis” a term describing the progression of
marine-derivative is the cytosine arabinoside (Ara-C) Fig. cellular events leading to necrotic cell death [76]. An in-
(1). Although the mechanism of action of cytosine arabi- creasing number of data show that although autophagy is
noside (Ara-C) is multifactorial, its active metabolite, Ara-C triggered to defend cell life, if the cell injury is protracted,
triphosphate (Ara-CTP), is the prototype of the competitive autophagy may degrade components essential for cell life
inhibitor of DNA polymerase, being Ara-C a structural ana- and therefore cause death [77]. Since autophagy may be in-
224 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Nastrucci et al.
volved both in tumor suppression and tumor cell survival 4. Combination of ET-743 with different drugs with an-
[78] more studies are needed to explain the role of autophagy timitotic effects, especially those which target cytoskele-
in tumor progression. Nevertheless, tumor cells seem sensi- tal elements, including (a) microtubule modulators such
tive to both autophagy inhibition [79] and autophagy stimu- as taxane drugs (e.g. taxol, paclitaxel, taxotere, do-
lation [80]. As suggested, an extensive mitophagy may in- cetaxel), podophylotoxins or Vinca alkaloids (e.g. vin-
duce mitochondrial membrane potential loss and irreversible cristine, vinblastine); (b) antimetabolite drugs such as 5-
cell death [81]. Since human normal cells seems more resis- fluorouracil, cytarabine, gemcitabine, purine analogues
tant to KF than tumor cells [75, 82], peculiar mechanism of (e.g. pentostatin, methotrexate); (c) alkylating agents,
action of KD may render this drug particularly interesting in such as nitrogen mustards (e.g. cyclophosphamide or
cancer therapy. ifosphamide); (d) drugs targeting DNA, such as the an-
tracycline drugs adriamycin, doxorubicin, pharmorubi-
Protein Kinase C (PKC) Inhibition cin or epirubicine); (e) drugs that target Topoisomerases,
such as etoposide; (f) hormones and hormone agonists or
In humans more than 500 kinases [83], a family of serine/
antagonists, as estrogens, antiestrogens (tamoxifen and
threonine kinases, interact in cellular metabolism and signal
related compounds) and androgens, e.g. flutamide, le-
transduction. Classically, PKC represent the target of the
uprorelin, goserelin, cyprotrone or octreotide; (g) drugs
potent tumor-promoting phorbol esters [84]. PKC isozymes
targeting signal transduction in tumor cells, including
include: conventional PKC (PKC(cid:2) (cid:3)(cid:1) /(cid:3)(cid:1)(cid:1), (cid:6)) calcium-
antibody derivatives, e.g. herceptin; (h) alkylating drugs,
dependent for their activation, novel PKC (PKC (cid:4), (cid:5), (cid:7), (cid:10))
like platinum drugs (cis-platin, carboplatin, oxaliplatin,
calcium- independent and atypical PKC (PKC(cid:11), 2(cid:9)/(cid:8)), which
paraplatin) or nitrosoureas; (i) drugs potentially affect-
does not bind phorbol esters or bryostatins. PKC(cid:5) is primar-
ing metastasis of tumors, such as matrix metalloprotein-
ily involved in proliferation and survival, while PKC(cid:4) is an
ase inhibitors; (j) gene therapy and antisense agents; (k)
important regulator of apoptosis. Thus PKC(cid:4) activation trig-
antibody therapeutics; (l) other bioactive compounds of
gers apoptosis [84,85].
marine origin, notably the didemnins, such as aplidine;
(m) steroid analogues, in particular dexamethasone; (n)
New Drug Development anti-inflammatory drugs, in particular dexamethasone;
Nowadays both the FDA and the EMA approved only and (o) anti-emetic drugs, in particular dexamethasone
two drugs: cytarabine (Cytosar-U1®) and Eribulin (Ha- [90].
laven®) in cancer treatment. Trabectedin (ET-743 or Yon- The above examples support the concept that when drugs
delis1®), which has been approved by EMA, is now complet- produce very similar agonistic effects (e.g. antineoplastic
ing Phase III studies for final approval by the FDA [7-9]. activity, lowering blood pressure, relieving pain, etc.) it may
Table 1 shows the most important MNPs in clinical trials be usual to use these drugs in combination. Combined effect
development. However, a great number of new compounds, may be quantitatively predictable when knowing the individ-
mainly synthetic derivatives, and drug combinations have ual drugs' and efficacy. This interaction is called “additive”.
been patented. Looking at relevant commonly used internet However, when the combination effect is higher than the
sites for patents, such as www.google.com/patents; predicted value, the interaction is defined "synergistic". Al-
www.uspto.gov; ternatively, when the value is less than expected is "antago-
http://ep.espacenet.com;www.freepatentsonline.com; www. nistic" [91]. Nonetheless, the combination of strong cyto-
wipo.int/pctdb/en/search-simp.jsp; www.freshpatents.com toxic agents requires often specific attention. This is particu-
some new and potentially important discoveries are high- larly true for MNPs that are some of the strongest acting
lighted. From a clinical point of view the association of drugs in therapy. Being characterized by: (I) complex phar-
MNPs that have been previously shown to be clinically well macological profiles (e.g. pharmacodynamic and pharma-
tolerated by patients and classical antitumor agents are par- cokinetic differences within and/or between patients), (ii) not
ticularly interesting. Different examples, recently patented, completely clarified mechanism of action, (iii) narrow thera-
are reported below. peutic window, (iv) sudden dose-toxicity curve, the combina-
1. Drug combinations comprising of Aplidin® or Aplidin® tion with other drugs require specific detailed studies. The
use of combination drugs relies on the observations that,
analogues with other antitumoral agents, and the use of
often, in oncology combination regimens are used since they
these combinations in the treatment of lung cancer,
are frequently favored over single agents especially those
breast cancer, colon cancer, prostate cancer, renal can-
cer, melanoma, multiple myeloma, leukemia and lym- using drugs with different mechanisms of action [92]. ET-
phoma. Potentiating activity is shown [86]. 743 in combination with pegylated liposomal doxorubicin
(PLD) is authorized by EMA since 28 October 2009 for the
2. Combinations of Aplidin® associated to another antican- treatment of patients with relapsed platinum-sensitive ovar-
cer drug selected from sorafenib, temsirolimus and ian cancer [93]. Indeed there is a documented benefit for the
sunitinib, together with the use of these combinations in combination ET-743+PLD in terms of progression-free sur-
the treatment of different xenografted tumors, including
vival consistent with published data of platinum-based regi-
NSCLC. Potentiating activity is studied [87].
mens [94]. However, as explained above, drug association
3. Docetaxel in combination with effective therapeutic can show both advantageous results as in the case of
concentrations of ET-743 [88]. Dexamethasone in com- ETS+PDL or in the case of Bryostain-1+vincristine in ag-
bination with ET-743 [89]. gressive non-Hodgkin lymphoma relapsing after an anti-
logous stem cell transplant [95] and harmful results, such as
Anticancer Drug from Sea Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 225
the combination Bryostatin-1+paclitaxel in advanced pan- transferase (OAT). This novel form of OAT is critically in-
creatic cancer [96] or +cisplatin in recurrent or persistent volved in a new pattern of spindle assembly, apparently not
epithelial ovarian cancer [97]. essential for normal cell division, since human patients, car-
rying inactivating mutations in the OAT gene, develop to
Finally, in Table 2 are reported a few but important re-
adulthood without any symptom while would be expected
cent US patents, for new newly-invented derived from ma-
from deficits in mitotic cell division [109]. This peculiar
rine organisms, in relation to their chemical synthesis, isola-
mechanism of action supports the lack of toxicity of Dia-
tion method, use and mechanism of action, in correspon-
zonamide A in normal cells and its antitumoral effect [108,
dence to their patent number [98-107].
109]. To date Diazonamide A is the only compound in pre-
Briefly, the US7256286 concerns the synthesis of simpli- clinical development. The US7947671 describes in vitro IC
50
fied bryostatin analogues. These compounds are useful as in different cancer cell lines of synthetisezd natural ecteinas-
bryostatin-like therapeutic agents, and in pharmaceutical cidins and related compounds [102]. The US8003802 con-
formulations and methods of treatment employing the same. cerns methods for synthesizing Salinosporamide A and its
Other compounds are useful a precursors in the synthesis of analogs. It relates to the total synthesis of chemical com-
such agents. The compounds of the present invention can be pounds, including heterocyclic compounds and analogs
readily synthesized on a large scale, and thus can be made thereof. Some embodiments are directed to the desired
readily available for commercial purposes as compared to chemical compound and intermediate compounds. Other
the low yields and environmental problems inherent in the embodiments are directed to the individual methods of syn-
isolation of bryostatins from natural sources [98]. The thesizing the chemical compound and intermediate com-
US7439265 reports the recommended doses for administra- pounds [103]. The US7576188 describes pharmaceutical
tion in animals and humans of Irciniastatins A and B. These compositions, pharmaceutical dosage forms, kits and meth-
two drugs appear to be powerful (IC 0.001 to <0.0001 ods for the treatment of cancer using aplidine and aplidine
50
μg/ml) murine and human cancer cell growth inhibitors. derivatives in combination therapies Treatment of leukemias
Both were isolated (10-3 to 10-4 % yields) by cancer cell line and lymphomas [104]. The US20090142331 concerns
bioassay-guided techniques. The dichloromethane-methanol method for the production of substances from the novel
extract exhibited strong (IC 10-2 μg/ml) activity against the Actinomycete Taxa MAR3A, MAR3B and MAR4. The meth-
50
P388 lymphocytic leukemia and a minipanel of human can- ods include disclosure of where these microorganisms can be
cer cell lines, including pancreas, breast, CNS, lung, colon obtained and their culture requirements. It also provides spe-
and prostate cell lines [99]. The US7759345 reports the in cific information describing characteristic DNA sequences
vitro IC in different cancer cell lines of different 217 de- that are used to identify members of this group and discloses
50
rivatives of ET-743 [100]. The US7622289 describes Dia- that members of this group produce metabolites with signifi-
zonamide [101]. Diazonamide A Fig. (4) shows a new cant activities in pharmaceutically relevant bioassays [105].
mechanism of action. Although it induces M-phase growth The US20110081690 shows, as primary object, an ecological
arrest in a variety of cancer cell types in a way reminiscent method of extracting TTX from mucus of nemertean worms
of those caused by tubulin poisons, no evidence of a direct allowing the animals to be kept alive and sustain mucus pro-
interaction between the compound and tubulin/microtubules duction. An object of the present invention is to provide an
in vitro has been reported [108]. Diazonamide A interacts optimal milieu in aquariums for a long-term survival of the
with a specifically proteolyzed form of ornithine (cid:1)-amino nemertean worms. An object of the present invention is to
Table 2. Some Examples of New US Patents for Marine-derived Drug.
US Number Patent Description of the Invention
US7256286 Bryostatin analogues, synthetic methods and uses98
US7439265 Irciniastatins A and B from the Indo-pacific sponge Ircinia ramosa99
US7759345 Antitumoral derivatives of ET-743 (217 compounds) 100
US7622289 Ornithine amino transferase inibitors starting from Diazonamide (tissue omogenate of the marine ascidian Diazona angulata) 101
US7947671 Synthesis of natural ecteinascidins and related compounds102
US8003802 Total synthesis of Salinosporamide A and analogs thereof 103
US7576188 Aplidine and aplidine analogues104
US20090142331 Method for the production of bio-active substances from the novel actinomycete taxa MAR3A, MAR3B and MAR4 belonging to
the family of treptomycetaceae105
US20110081690 Sustainable method for synthesizing tetrodotoxin (TTX) 106
US20100331370 Novel isobenzofuran analogs of sclerophytin A107
226 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Nastrucci et al.
provide an optimal milieu in aquariums, by supplying the However, large studies on Bryostatin-1's mode of action
aquarium with continuous inflow of deep-sea water. An ob- and structural optimization as a therapeutic agent were ham-
ject of the present invention is to provide a method of con- pered by its limited availability from natural sources and by
tinuously adding the mucus of nemertean worms to the fer- the complexity of its structure making its synthesis challeng-
mentation-process of the TTX-production. Other objects and ing. For these reasons the recent complete synthesis of Bry-
advantages of the present invention will become obvious to ostatin-1 in 2011 (see Table 2 for the US patent) was an ex-
the reader and it is intended that these objects and advan- tremely important achievement [98, 115].
tages are within the scope of the present invention [106]. The
Indeed, it is important to keep in mind that the same ma-
US20100331370 reports in vitro IC in different cancer cell
50 rine derivative drug may have different molecular targets.
lines. A structurally novel set of analogs has been developed For instance Aplidin® (Plitidepsin), a synthetic didemnin
based on the isobenzofuran bicycle common to most of the
second-generation, acts through modulation of different tar-
2,11-cyclized cembranoids that exhibit IC 's as low as 1μM
50 gets, such as epidermal growth factor receptors, non-receptor
for growth inhibition against KB3 cells. Analog 10h pos-
protein-tyrosine kinase SRC, vascular endothelial growth
sesses sub-micromolar growth inhibitory activity against the
factor and Rac1 [116]. Moreover, Gemcitabine, as well as
RPMI-8226 leukemia and HOP-92 non-small cell lung can-
Ara-C, can also work on Topoisomerase I. Thus, incorpora-
cer cell lines. The present invention is now described with
tion of gemcitabine or Ara-C into DNA can trap Topoi-
reference to certain examples, which explain but do not limit
somerase I cleavage complexes. However, in contrast to Ara-
it [107].
C, the structural conformation of Gemcitabine enhances the
stability of Topoisomerase I cleavage complexes, generating
CURRENT & FUTURE DEVELOPMENTS
DNA-strand breaks by interference with advancing replica-
For many decades drug discovery has been based on the tion or transcription forks [117]. All of these characteristics
concept ‘one-disease-one-target-one-drug’ strategy in are important for a good “lead”. Often, when a designed
searching for the ‘magic bullets’. Several highly specific “lead” fails to work at the designed target it is discharged
drugs, having only one target, are highly useful in monotar- and a new one is searched for and analyzed, with great waste
get medicine and provided important successes, for instance of human and financial resources. Instead, the discarded
the (cid:1)1a-adrenoceptor antagonist drugs (e.g. Tamsulosin®) or molecule may be a good inhibitor or activator of other bio-
the selective cyclooxygenase-2 inhibitors (e.g. Celecoxib®). logical targets involved in human pathogenesis patterns. Ma-
Currently, the rational design of ligands that act on specific rine derivatives drugs may be useful lead candidates in this
multiple targets approaches is preferred. Marine-derivatives new philosophy of drug discovery, in a way “recycling”
drugs often are characterized to work in different and unre- promising compounds for different uses from the ones origi-
lated diseases or to have different molecular targets. This is nally intended.
the case of Bryostatin, Aplidin or Gencytabine. Thus, Bry-
The strength of the marine pharmaceuticals pipelines is
ostatin-1, developed as anticancer agent, has shown to be supported by three drugs (Cytarabine, Yondelis® and Ha-
active in different diseases other than cancer [110, 111]. laven®) approved by FDA and/or EMA, seven compounds in
Bryostatin-1 belongs to a unique class of high-affinity PKC Phase II trials and six compounds in Phase I trials (Table 1)
ligands (e.g. activation of PKC with subsequent down- as well as different products being investigated at preclinical
regulation) [112]. It is generally accepted that Bryostatin-1
level, as the next possible clinical candidates Fig. (4) [116,
arouses an early short activation and self-phosphorylation of
118].
PKCs that in turn determines membrane translocation of
Nevertheless, few marine derived drugs are available on
PKCs and subsequent PKCs down-regulation. Specifically,
the market to date. Different reasons may be accountable for
Bryostatin-1 Fig. (2) shows a unique pattern of down regula-
this shortfall. The most important reason is the lack of suffi-
tion of PKC(cid:4) isozyme, characterized by a down regulation at
low concentrations and a mechanism of protection from cient amount of natural product. Enough to think that the
down regulation at higher concentrations [112]. This prop- production of bryostatin-1 for clinical use by its marine
erty makes Bryosatin-1 an attractive drug. Thus, in all the source organism, Bugula neritina, provided only 18g of pure
Bryostatin-1 from 14t (tons) of the producing bryozoan
systems in which PKC(cid:4) plays an antiapoptotic role, such as
(0.00014%) [119]. The introduction of mariculture of the
cancer, Bryosatin-1 may induce cell cytotoxicity. However,
Bugula neritina has allowed a successful production of bry-
low concentrations of Bryostatin-1 can be useful in diseases
such as Alzheimer, in which reduced PKCs activity is ob- ostatin 1 [120]. Recently, the full synthesis for Bryostatin-1
served [113]. A recent study shows that Bryostatin-1, acti- was reported [115], as well as a synthetic and more accessi-
vating both PKC(cid:5) and PKC(cid:2), prevents an augment of solu- ble functional analogue of Bryostatin-1 that targets PKC
isoforms, major targets of therapeutic interest [121].
ble (cid:3) amyloid protein (A(cid:3)), that in turn suppresses PKC(cid:5)
and PKC(cid:2) expression causing synaptic loss and memory Among the different reasons accounting for the few
deficits before amyloid plaque deposition in Tg2576 Alz- number of sea drugs available, there are also:
heimer transgenic mouse strain [110].
i). Difficulties in accessing the source of the samples.
Moreover, Bryostatin-1, at low nanomolar concentra- Some of the drug-producing organisms live in the deep
tions, strongly reactivates latent HIV-1 infection in mono- sea, for example the Caribbean marine sponge Dis-
cytic and lymphocytic cells via activation of PKC(cid:1)(cid:2) and codermia dissoluta, the source of discodermolide lives
PKC-(cid:4) [37]. This ability of Bryostatin-1 is important since at 140 m (330ft) under the sea. Other organisms live
latent viral reactivation is essential for the activity of current only in specific areas, such as the sea squirt Ectenais-
antiretroviral therapy [114].
Anticancer Drug from Sea Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 227
cidia turbinate, the source of ecteinascidin, which lives vii). Compliance with European and International Marine
only in marine mangrove environments [122]. Protection standards and laws, such as those regulated
by the IMO - the International Maritime Organization -
ii). Problems in harvesting the product and synthesizing the
which is the United Nations specialized agency with re-
compounds in enough quantity to use, difficulties in iso-
sponsibility concerning also the prevention of marine
lation and purification procedures, high toxicity of the
pollution by ships [126] and EU Directives, such as the
active compound, ecological considerations, government
the Directive 2008/56/EC, also called the “Marine Strat-
policies, lack of infrastructure and insufficient capital
egy Framework Directive” [126, 127], aiming also at the
investment are only some of the issues involving the use
protection of the marine environment and its inhabitants.
of marine environment derided compounds. In the case
of Bryostatin-1 or ecteinascidin, for example, over 1 Drug discovery implicates different steps [128]; some
tonne of the sea squirt Ectenaiscidia turbinate have to important ones, involved in the search for bioactive compo-
be harvested to produce just 1g of the drug [123]. nents from marine sources, are summarized in the schematic
Fig. (5).
iii). Difficulties in discovering and validating the target.
Some compounds show very peculiar mechanisms of ac-
tion, such as ectenainascidin (see above) or Kahalide

(see above), or have multi-target diseases properties,
Worldwide marine
such as Bryostatin-1 (see above).
organism collection
iv). Difficulties in identifying the “hit” compound from the
Drug Discovery
crude extract.

v). Difficulties in discovering the “lead” compound. Thus

high quality leads are compounds that already satisfy Target Identification
some of the five criteria established in 1997 for a future
drug candidate [124], such as: molecular weight less
Target Validation
than 500g/mol, a partition coefficient (logP - a measure

of hydrophobicity), less than 5, no more than five hy-
drogen bond donors and no more than 10 hydrogen bond Hit Identification
acceptors. Keeping the molecular weight under 500 has

become particularly difficult because broad synthetic ef-
forts naturally tend to increase the size of the chemicals. Hit to Lead
vi). Difficulties in synthesizing the compounds related to the
large structural diversity and complexity of natural Lead optimization

drugs derived from the marine environment and hurdle
and complexity in performing the several steps required
to reach the target molecule. The short asymmetric total Lead Development

synthesis of Bryostatin 1 needed more than 40 steps
[115]. The large structural diversity of marine natural
Clinical Development
compounds make their isolation and purification very

difficult and the development of novel anticancer drugs
from these natural sources carries problems that are not
usually encountered when dealing with synthetic com- FDA-EMA Approval
pounds. One of the alternatives could be a semisynthetic

approach to enhance the yield of lead natural com-
pounds. This can be achieved by modifying just the Fig. (5). A simplified representation of the rational steps necessary
functional groups of existing natural compounds and for drug development that have been designed in the recent years
this would potentially lead to the generation of structural using technological advances.
analogues with greater pharmacological activity and The first step is sample collection that may be difficult to sustain
fewer side effects. Advances in the field of proteomics, for organisms living in the marine environment (e.g. sponges, bryo-
genomics and metabolomics are related to cell metabo- zoans). The occurrence of symbionts (e.g. fungi, bacteria, microal-
lism and have a great impact on the discovery of new gae) living on or inside the macroorganisms make sample collection
antitumor targets. Not only this, there are newer fields of more complicated.
biology, such as pharmacogenomics and pharmacoge- In the second step, the number of samples screened increases the
netics, which are proving very useful to assess patient probability of discovering valuable active metabolites. The selec-
susceptibility to specific pharmacological agents. Ebada tion of these compounds should be ideally based on fast, inexpen-
et al. in 2008 [125] described different methods for sive and representative primary tests. Once the valuable compound
“bioactivity-guided isolation, purification and identifica- has been discovered, different processes, such as selective extrac-
tion of secondary metabolites from marine invertebrates, tion, chromatographic fraction and final purification, are needed in
such as sponges, tunicates, soft corals and crinoids” order to obtain pure active compounds that will undergone structure
[125]. elucidation, chemical modifications, structure-activity relationship
studies, synthesis and biosynthesis. These steps will follow the