Comprehensive Natural Products II Vol.2 Natural Products Structural Diversity-II

718 Pages·2010·27.35 MB·English

by  Mander L., Liu H.-W.B.

2.01 Overview and Introduction
BradleyS.Moore,UniversityofCaliforniaatSanDiego,LaJolla,CA,USA
PhillipCrews,UniversityofCaliforniaatSantaCruz,SantaCruz,CA,USA
ª2010ElsevierLtd.Allrightsreserved.
Extendingknowledgeandprinciplesofstructuralchemicaldiversityisoneimportantoutcomederivedfrom
thecomprehensivestudyofnaturalproducts.The19chaptersofthisvolumeprovideaneye-catchingglimpse
of some past landmark discoveries, a synopsis of the current discovery strategies, and prospects for future
advances.Theperspectivesprovidedherearerichinoverviewsofunusualscaffoldsproducedfromterrestrial
and marine organisms that are especially robust in machinery to biosynthesize unusual compounds. We are
confidentthatsubstantialrewardswillbegainedforreadersengagedinthecarefulstudyofthesynopsesthat
follow.Itisalsonoteworthythatthiscollectionprovidesanorthogonalviewofthenaturalproductsstructural
diversitypresentedinVolume1,whichwasorganizedlargelyonbiosyntheticgrounds.
Thepotentialofmolecularstructurestopopulatestructuralchemicalspaceisdiverseandthechallengeisto
make new discoveries that add to the accumulated knowledge base. An important milestone was achieved
during the assembly of this volume and it involves the registration, in 2008 by Chemical Abstracts Service
(CAS),ofthe40millionthchemicalsubstance.However,arathersurprisingoutcomewasdeducedbyaCAS
team leadbyLipkus; histeamanalyzed theseframeworks andconcludedthat‘‘halfofthecompounds canbe
describedbyonly143frameworkshapes’’.Therigorousstudyofnaturalproductsprovidesanoptimalwayto
expandsuchunderstandingandsuchaprospectisamplyillustratedbythe19chaptersinthisvolume.
Therateofnewcompounddiscoveryisonanupwardtrajectory;worldwidemorethan200newcompounds
arediscoveredperhour.Atopicofsubstantialgeneralinteresttochemistryandbiologyprofessionalsinvolves
assessmentandutilizationastoolsforfurtherinquiryofthestructuraldiversitypresentinbothsyntheticand
natural products. Each chapter in Volume 2 illustrates the pathways and methods useful in the discovery of
natural products, many of which possess previously unexplored molecular structure domains. Each chapter
presentsaccountsonbiosyntheticproductspossessinghighatomdiversity,intriguingelementsofchirality,or
structuresdenselysprinkledwithfunctionality.Overall,thesechaptersdepicthundredsofmolecularstructures
andareroughlydividedintoeighttopicalareas.
Thetraditionaltargetsfornaturalproductsdiscovery–terrestrialplants,marinemacroalgae,andarthopods–
areexaminedinChapters2.02–2.04.Theimportantroleplayedbyplantnaturalproductsinthedevelopmentof
therapeuticstotreatawiderangeofdiseasesisoutlinedinChapter2.02.Morethan29significantnaturalproducts
arediscussed,includingsuchwell-knowncompoundsastaxol,thevincaalkaloids,prostratin,resveratrol,andthe
ginkgolides.Thelasttwoofthesethreechaptersaresharplyfocusedonmarineandterrestrialnaturalproducts.
Descriptionsofnewconnectivitypatternsarehighlighted,butevenmoreimportant,arethefascinatingcontrasts
inmarineversusterrestrialchemicalecologymechanismsthatcanbegleanedfromside-by-sidereadingofthese
chapters.
Significant natural products continue to be derived from microorganisms and this is the focus of five
successive chapters, Chapters 2.05–2.09. The pioneering work of Professor Waksman on soil-derived actino-
mycetes,asourceofthemajorityofnaturalantibiotics,providesthelaunchingpointfortherichdiscussionsthat
follow in Section 2 of this volume. The so-called ‘antibiotic of last resort’, vancomycin (C H Cl N O ),
66 75 2 9 24
discoveredinthe1950s,isrepresentativeofcomplexstructureselaborated byfilamentous bacteria.Similarly
significant milestone natural products serve as anchor points for the remaining chapters. Some examples
include (1) cyrptophycin (C H ClN O ) from cyanobacteria, (2) epothilone A (C H NO S) from myx-
35 43 2 8 26 39 6
obacteria,(3)thediketopiperizeNPI-2538beingexploredinaUSanticancerclinicaltrial,whosestructureis
basedonhalimide isolated from amarine-derivedfungus,and(4)thestructurally complexamphidinolide M
1
2 OverviewandIntroduction
(C H O ), a potent cytotoxin (IC ¼0.05ngml(cid:2)1 vs. L1210 murine lymphoma cells) and lead structure
43 66 6 50
amongsignaturecompoundsofmarinedinoflagellates.
Theprolificsourcesofmarinenaturalproducts,sponges,andgorgonians areexploredinthenextsection,
Chapters2.10–2.11.Alargepercentageofmarinenaturalproductsaresponge-derivedandattentionisdevoted
to five major groups of secondary metabolites obtained from sponges. Another important topic involves
structures that are leads for human disease therapeutics. At the top of this list are polyketides such as
halichondrin B, spongiastatin-1, and discodermolide. A flavor of the diverse array of natural products that
can be encountered from octocorals can be gained from the chapter dealing with just one genus,
Pseudopterogorgia.Atotalof243substancesdividedinto19chemotypeshavebeendiscoveredfromthissource
between1968and2008.
Theapplicationofmoleculargeneticstonaturalproductsdiscoveryoffersrichrewards.Thistopic,along-
side the results of employing synergistic stimuli to upregulate natural product biosynthetic pathways, is
explored in the next set of three chapters, Chapters 2.12–2.14. Genome sequencing offers a glimpse into the
molecularblueprintofanorganismandbyreadinganddecodingthisinformation,chemistscanemploycleaver
methods to extract new metabolites from cultured organisms (Chapter 2.12) as well as from uncultured
environmental communities (Chapter 2.13). For instance, the genome sequence of Streptomyces coelicolor A3(2)
deduced in the year 2002 revealed that this model actinomycete bacterium has the genetic capacity to
synthesize two dozen natural products, most of which at the time were of unknown molecular composition
buthavesincesuccumbedtostructureelucidationtoyieldnewchemicalentities.Thispowerfulcombinationof
genomicsandnaturalproductchemistryhasfurthermorebeensuccessfullyappliedtoprobeintimatesymbiont
interactionsininsectsandmarineorganisms(Chapter2.14).
Great structural diversity is possible from the combinatorial combination of natural and unnatural amino
acids.Naturehasusedthisasatemplatetoformpowerfullyactivenaturalproducts.Therichnessofmolecular
structurescoupledwithphysiologicalactivityisthefocusofChapters2.15and2.16.Adazzlingarrayofpeptide
toxins from the venoms of cone snails and sea anemones is illustrated in Chapter 2.15 that will provide the
readerwithacomprehensiveappreciationfortheirdistribution,diversity,neuropharmacology,andtherapeutic
applications. Marine tunicate cyclic peptides were the inspiration for the discovery of a new family of
ubiquitous peptides from symbioticaswell asfree-living cyanobacteria called cyanobactinsthatcomplement
thefascinatingassortmentofhighlymodifiedribosomalpeptidesderivedfrommicroorganisms.
Thefinalsectionsofthisvolumetreatthreecomplementarytopics.Chapter2.17outlinestheapplicationof
insights from bioinformatics and molecular genetics to explore new chemical structural space relative to
macrolides and cyclic peptides. The task of total structure elucidation is a core activity of natural products
chemistryanditisimportantthatthisbecompletedinanunequivocalfashion.Thetrialsandtribulationsofthis
taskareexploredinChapter2.18throughthediscussionofillustrativecaseexamplesofstructureelucidations
gonebad.SomewhatsurprisingisthefollowingpassagefromChapter2.18:‘‘Bytheendof2008,morethan200
structurerevisionsformarinenaturalproductshavebeenreported.’’Thefinaltwochapters,Chapters2.19and
2.20, return to natural products and therapeutics. These ideas were explored in the opening chapter and
intriguingnewdimensionsareexploredtherein.
The topics of this volume amply illustrate the structural diversity of both terrestrial and marine natural
products.Weknowthatthereaderwillgaininsightsfromthestudyofpastmilestonedevelopmentsaswellas
pitfallsinexperimentaldesign.Thecriticalroleofdereplicationinmodernstructureelucidationisalsoamply
illustrated.Oncetheknowledgebaseisinhandfromthesechapters,wetrustthatmanyreaderswillbeinspired
todesignandapplynewexperimentaldirectionsforfuturestudies.
OverviewandIntroduction 3
BiographicalSketches
Bradley S. Moore is currently professor of oceanography and pharmaceutical sciences at the
ScrippsInstitution of Oceanography and the Skaggs SchoolofPharmacy andPharmaceutical
Sciences at University of California, San Diego. He was first introduced to natural product
researchasachemistryundergraduatestudentattheUniversityofHawaii,whereheexploredthe
chemistryandbiosynthesisofcyanobacterialnaturalproductswiththelateProfessorR.E.Moore.
Fascinatedbythebeautyandcomplexityofnaturalproductstructures,hewentontoconduct
graduate (Ph.D. 1994 in bioorganic chemistry with Professor H. G. Floss at the University of
Washington)andpostdoctoralresearch(1994–95withProfessorJ.A.RobinsonattheUniversity
of Zu¨rich) on the biosynthesis of bacterial natural products in order to explore how nature
assembles complex organicmolecules. Prior to moving to the University of California at San
Diegoin2005,heheldacademicappointmentsattheUniversityofWashington(1996–99)and
theUniversityofArizona(1999–2005).Hisresearchinterestsinvolveexploringandexploiting
marinemicrobialgenomestodiscovernewbiosyntheticenzymes,secondarymetabolicpathways,
andnaturalproductsfordrugdiscoveryanddevelopment.
Phillip Crews is currently distinguished professor of chemistry and biochemistry at the
University of California at Santa Cruz. His training included a B.S. in chemistry from the
UniversityofCaliforniaatLosAngeles,andaPh.D.inorganicchemistryfromtheUniversity
of California at Los Angeles. He engaged a year of postdoctoral research at Princeton
University,supportedbyaNationalScienceFoundationFellowship.Hisentireindependent
academiccareerhasbeenattheUniversityofCaliforniaatSantaCruz.Earlyinhistermasan
assistant professor he began, without prior training, a program in marine natural products
chemistrythatrequireda10-yearincubationtobecomesuccessful.
Research in the Crews lab emphasizes innovative approaches to the study of marine
naturalproductschemistry.Duringthethirtyyearshisprogramhasmaturedandisregarded,
on an international level, as among the most active and productive in this subject area.
4 OverviewandIntroduction
The effectiveness of his efforts continues to be based on a foundation of multifaceted
discoveries. The Crews group emphasizes a field-driven approach to explore and discover
inspirationalchemicalstructuresoftenaccompaniedbysignificantbiologicalactivityderived
from marine sponges. Several years ago the lab expanded investigations to encompass the
studyofmarine-derivedfungi.
The most important new compounds that the Crews lab have published are those that
exhibit anticancer activity and/or action against relevant molecular targets, or function as
important molecular probes. Significant examples (but not an exhaustive list) of these new
biomolecules first discovered at the University of California at Santa Cruz include benga-
midesAandB,jasplakinolide,fijianolidesAandB,mycothiazole,plakinidinesAandB,the
psammaplins,asparazine,themilnamides,psymberin,leucosolenaminesAandB,theRHMs,
and efrapeptin polypeptides. Several of these compounds have been the seed for further
therapeutic development. The synthetic compound, LAF380, developed as a bengamide A
analogue entered cancer clinical trials in 2000. Though the trials were subsequently sus-
pended, other bengamide congeners are being evaluated for their potential as anticancer
drugs.Thefijianolides,psymberin,andefrapeptinGhaveshownpositiveinvivoresponsesat
theFordCancerCenterandabroad-basedcampaignhasbeguntofurtherexploittheclinical
potential of these agents. One additional noteworthy development is our lab continues to
supplyimportantactininhibitors,jasplakinolideandlatrunculinA,toinvestigatorsthrough-
out the world to facilitate its use as a molecular probe. For the last decade, more than 200
publications have appeared annually based on the use of both compounds in cell biology
research.
2.02 Terrestrial Plants as a Source of Novel Pharmaceutical
Agents
GordonM.CraggandDavidJ.Newman,NCI-Frederick,Frederick,MD,USA
DavidG.I.Kingston,VirginiaPolytechnicInstitute&StateUniversity,Blacksburg,VA,USA
ª2010ElsevierLtd.Allrightsreserved.
2.02.1 Introduction 5
2.02.2 PlantsasaSourceofBioactiveCompounds 6
2.02.3 AnticancerCompounds 6
2.02.3.1 VincaAlkaloids 6
2.02.3.2 Podophyllotoxin,Etoposide,andTeniposide 7
2.02.3.3 CamptothecinandAnalogues 8
2.02.3.4 Combretastatins 9
2.02.3.5 Homoharringtonine 10
2.02.3.6 TaxolandItsAnalogues 10
2.02.3.7 PlantSaponins 13
2.02.3.8 Triptolide 14
2.02.3.9 Protopanaxadiol 15
2.02.3.10 Ingenol-3-Angelate(PEP005) 15
2.02.3.11 Phenoxodiol 16
2.02.3.12 Flavopiridol 16
2.02.3.13 (cid:2)-Lapachone(ARQ501) 17
2.02.3.14 AdenineDerivatives:Olomucine,Roscovitine,andAnalogues 17
2.02.3.15 OtherActiveCompoundsinPreclinicalDevelopment 18
2.02.4 Anti-HIVAgents 22
2.02.4.1 MichellamineB 22
2.02.4.2 TheCalanolides 23
2.02.4.3 Prostratin 24
2.02.4.4 BetulinicAcid 24
2.02.5 AntimalarialCompounds 25
2.02.5.1 Quinine 25
2.02.5.2 Artemisinin 26
2.02.6 CardiovascularandMetabolicDiseases 26
2.02.6.1 Resveratrol 26
2.02.6.2 HoodiaCompounds 27
2.02.6.3 (cid:2)-AdrenergicAmines:Ephedrine,Propranolol,Atenolol,andMetoprolol 28
2.02.6.4 DigoxinandRelatedCardiacGlycosides 28
2.02.7 CNSActiveAgents 29
2.02.7.1 HuperzineA 29
2.02.7.2 Ginkgolides 30
2.02.7.3 St.John’sWort 30
2.02.7.4 SalvinorinA 31
2.02.8 OutlookandFutureProspects 32
References 32
5
6 TerrestrialPlantsasaSourceofNovelPharmaceuticalAgents
2.02.1 Introduction
Thestudyofnaturalproducts,or‘Nature’sCombinatorialLibrary’,hashadalonghistoryasasourceofdrugs,
andplantshavehistoricallybeenattheforefrontofnaturalproductdrugdiscovery.Intheanticancerarea,for
example,vinblastineandvincristine,etoposide,paclitaxel(Taxol),docetaxel,topotecan,andirinotecan,among
others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial
therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant
products.Thischapterprovidesanoverviewofthemajormedicinalagentsthatarethemselvesnaturalproducts
isolatedfrom plantsorarechemicalmodificationsofsuchleadcompounds.Itcoversthetherapeuticareasof
cancer,HIV,malaria,cardiovascular,andcentralnervoussystem(CNS)diseases.Naturalplantproductshave
also made contributions in areas such as immunomodulatory1–3 and antibiotic activities,4–6 and the reader is
referredtothecitedreviewsforinformationontheseareas.
2.02.2 Plants as a Source of Bioactive Compounds
Plants have historically been the most important source of novel bioactive natural products, for obvious
practical reasons. It is much easier to identify and collect biomass from a tree or shrub than to culture and
identify a microbial species, or to dive into the ocean to collect marine organisms. It is thus thoroughly
understandablethatthevast majorityof natural products discovered before about the mid-twentieth century
wereofplantorigin.Inadditiontotherelativeeaseofcollectionofplantbiomass,plantsoftenhaveatradition
of use as phytomedicines, and this tradition can guide the selection of plant materials to be investigated.
Theimportanceofplantsasasourceofanticanceragentshasbeensummarizedrecently7andadiscussionofthe
valueofnaturalproducts tofuturepharmaceutical discoverypoints outthat‘‘natural products havebeenthe
major source of chemical diversity for starting materials for driving pharmaceutical discovery over the past
century.’’8Finally,acomprehensivereviewwithover800referencestonaturalproduct-derivedcompoundsin
clinicaltrialshasalsoappearedrecently.9Althoughthereviewscitedcovernaturalproductsfromallsources,
theydoincludemanyexamplesofplant-derivedcompoundsinclinicaluseorasleadstoclinicaldevelopment,
andthusservetohighlighttheimportanceofplantnaturalproductsasasourceofbioactivecompounds.
2.02.3 Anticancer Compounds
2.02.3.1 VincaAlkaloids
Thevincaalkaloidsvinblastine(1)andvincristine(2)werethefirstnaturalproductstoenterclinicaluseasanticancer
agents.TheywereisolatedindependentlyfromtheplantCatharanthusroseusG.Don(thenknownasVincaroseaL.,
whencethecommonnameofthealkaloidscame)bytworesearchgroupsinthelate1950sandearly1960s.Onegroup
wasthatofRobertNobleandCharlesBeerattheUniversityofWesternOntarioandtheotherwasthatofGordon
SvobodaatEliLillyandCompany.Interestingly,theCanadiangroupwasactuallylookingforantidiabeticagentsand
discoveredtheanticanceractivityofvinblastinebyacombinationofgoodluckandastutereasoning.10
TerrestrialPlantsasaSourceofNovelPharmaceuticalAgents 7
Themechanismofactionofthevincaalkaloidsisthatoftheinhibitionofthepolymerizationoftubulinto
microtubules. The cellular protein tubulin, which occurs in (cid:3)- and (cid:2)-forms, is essential for proper cellular
function. During mitosis tubulin polymerizes to form microtubules, which are long tube-shaped protein
polymers. The equilibrium between unpolymerized (cid:3)- and (cid:2)-tubulin and microtubules is an important one
and any disruption of this equilibrium can send dividing cells into mitotic block and apoptosis.11 The vinca
alkaloidsbindto(cid:2)-tubulinatadifferentsitefrompaclitaxel(Taxol)andacttopreventtubulinassembly.
Vinblastineandvincristinehavebeenusedclinicallyformanyyears.Themajorimportanceofvinblastineis
aspartofacombinationtreatmentforHodgkin’sdisease,whilevincristineisusedincombinationchemother-
apyofacutelymphoblasticleukemiasandlymphomas.12Severalanaloguesofthevincaalkaloidshaveentered
clinical useorclinical trials,includingvindesine (3),13vinorelbine(4),14thenaturallyoccurringanhydrovin-
blastine (5),andvinflunine (6).10,15Several synthetic approaches to thevincaalkaloids havebeen developed,
especiallybyKuehne,16whilestudiesofthechemistryofthealkaloidsinsuperacidicmediahaveyieldednew
alkaloidssuchasvinflunine.15
2.02.3.2 Podophyllotoxin,Etoposide,andTeniposide
The resin product obtained by extraction of the dried roots and rhizomes of the North American plant
Podophyllum peltatum L. (the American mandrake or mayapple) and of the related Indian species Podophyllum
emodiWall.ExRoyleisknownaspodophyllinandhaslongbeenknowntopossessmedicinalproperties.The
major active substance in podophyllin is the lignan lactone podophyllotoxin (7) although a variety of other
lignansandlignanglycosideshavealsobeenisolatedfrompodophyllin.17
8 TerrestrialPlantsasaSourceofNovelPharmaceuticalAgents
Podophyllotoxinhaspotentcytotoxicactivityandalsoactsasaninhibitoroftubulinpolymerizationbutitis
too toxic to be useful as an anticancer agent. Fortunately, scientists at Sandoz, Ltd. studied the chemistry of
podophyllotoxin glycosides and these studies led to the discovery of the semisynthetic podophyllotoxin
analoguesetoposide(8)andteniposide(9).Boththesecompoundsarecharacterizedbyhavinga49-hydroxyl
group and a glycoside substituted at the 4-epi-position. Etoposide is approved for the treatment of testicular
cancer and both drugs are used for a variety of cancers.18 Both etoposide and teniposide are only sparingly
solubleinwaterandsotheprodrugetopophos(10)wasdevelopedtoprovideamoresolubleformofetoposide;
ithasasimilarpharmacologicalprofiletoetoposide.19
Interestingly, the modes of action of etoposide and teniposide differ markedly from that of the parent
compoundpodophyllotoxin.ThesecompoundsarrestcellsinthelateSandG2phaseofthecellcycleandhave
noeffectontubulinassembly.Instead,theyinducesingle-strandbreaksinDNA(etoposide)orintheDNAin
L1210cells(teniposide).20–22Inthecaseofteniposide,thesebreaksarepredominantlydouble-stranded.These
effects are due to the ability of these compounds to inhibit DNA topoisomerase II (topo II).23 DNA topoi-
somerases are enzymes that allow DNA to coil and uncoil (i.e., change its topology), which is a necessary
preludetomitosis.ThetopoIImediatesdouble-strandbreaksbyformingacomplexwithDNA,theso-called
cleavable complex. Etoposide stabilizes this complex and inhibits the enzyme, thus leading to double-strand
breaksandultimatelytocelldeath.24
Numerouspodophyllotoxinanalogueshavebeenpreparedinattemptstodevelopimproveddrugsandthe
three new derivatives GL-331 (11),25 NK 611 (12),26 and TOP-53 (13)27 illustrate some of the leading
candidates to emerge from this work. The development of these and other podophyllotoxin analogues has
been reviewed.28,29 In spite of extensive synthetic work, the natural product podophyllotoxin remains the
preferredsourceofalltheanaloguesdevelopedtodate.
2.02.3.3 CamptothecinandAnalogues
Thealkaloidcamptothecin(14)wasdiscoveredinthemid-1960sbytheteamofMonroeWallandMansukh
WaniattheResearchTriangleInstituteinNorthCarolina;thiswasthesameteamthatdiscoveredtaxol(now
knownaspaclitaxel)afewyearslater.CamptothecinwasobtainedfromextractsoftheChinesetree,Camptotheca
acuminataDecne.,1873,anditshowedgoodactivityagainstL1210leukemia.Itwashoweververyinsolublein
water and this led to the clinical studies that were carried out on its water-soluble ring-opened sodium salt.
Unfortunately,thesetrialsrevealednumerousproblems,connectedinlargepartwiththelackofactivityofthe
ring-opened form. The trials were thus suspended30 and the development of this compound was delayed for
severalyears.
Fortunately, studies on camptothecin continued in some laboratories and it was discovered that it had a
previously unknown mechanism of action, namely the ability to inhibit topoisomerase I (topo I).31 The
topoisomerases I and II are enzymes that allow chromosomal DNA to undergo changes in topology
(i.e., relaxation) prior to replication. Camptothecin was found to inhibit topo I but not topo II, and to do so
TerrestrialPlantsasaSourceofNovelPharmaceuticalAgents 9
bybindingtothetopoIcovalentbinarycomplex.31Camptothecinwasthefirstcompoundfoundtoinhibittopo
Iasopposed to topo II,anditthus complements drugs suchasthepodophyllotoxin analoguesetoposide and
teniposide,whichinhibittopoII(Section2.02.2).Thismechanismisconsistentwiththefactthatcamptothecin
is capable of inhibiting DNA synthesis leading to cell death during the S phase of the cell cycle.32 It is
noteworthythatcamptothecinshowsremarkablespecificityinbindingonlytothecleavablecomplexformed
betweentopoIandDNA;itdoesnotbindtoDNAaloneortotopoIalone.AlthoughtopoIisanenzymefound
inallcelltypes,itslevelsareelevatedintumorsofthecolon,ovary,andtheprostrate,andthisispresumablya
significantpartofthereasonfortheeffectivenessofthecamptothecinanaloguesagainstthefirsttwoofthese
tumors.33
This discovery significantly increased interest in the compound and led to the synthesis of a number of
water-soluble analogues, which ultimately led to the development of the camptothecin analogues topotecan
(Hycamtin) (15) and irinotecan (Camptosar) (16), both of which have been approved for clinical use.
Topotecanisusedassecond-linetherapyforadvancedovariancancerinpatientswhohavefailedtorespond
totreatmentregimensthatincludeplatinumorpaclitaxel,whileirinotecanhasbeenapprovedforthetreatment
ofadvancedcolorectalcancer.
Manyotheranaloguesofcamptothecinhavebeenprepared.Studiesofcompoundsmodifiedonthequino-
lineringsystemhaveshownthatsubstitutionsatC-11andC-12normallyresultinareductionofactivity,while
substitutionsatC-7,C-9,andC-10canleadtoenhancedactivity.34TheE-ringlactoneisimportantforactivity
and almost all modifications to this ring have led to less active compounds; the homocamptothecins, with an
expandedringE,representanimportantexception.34
Asurveyofthedistributionofcamptothecinanditsmetaboliteshasbeenpublished.35Thecompoundsare
still obtained from the bark and seeds of C. acuminata and Nothapodytes foetida. Recent studies with hairy root
cultures of C. acuminata and Ophiorrhiza pumila indicate that plant tissue culture methods of production may
provefeasibleinthefuture.35
2.02.3.4 Combretastatins
Thecombretastatins,suchascombretastatinA-4(17a),areafamilyofstilbenes,whichwereisolatedfromthe
SouthAfrican‘bushwillow’Combretumcaffrum(Eckl.&Zeyh.)Kuntze,collectedinSouthernAfricainthe1970s
aspartofarandomcollectionprogramfortheUSNationalCancerInstitute(NCI)bytheUSDepartmentof
Agriculture(USDA),workingincollaborationwiththeBotanicalResearchInstituteofSouthAfrica.36Theyact
asantiangiogenicagents,causingvascularshutdownintumorsandresultingintumornecrosis.37Poorsolubility
ofcombretastatinA-4inaqueousmediaprecludeditsadvanceddevelopmentbutthewater-solubleanalogue,
combretastatinA-4phosphate(CA-4P;Zybrestat;R¼PO Na ,17b),hasreceivedorphandrugstatusfromthe
3 2
USFoodandDrugAdministration(FDA)forthetreatment ofarangeofthyroidcancersandovariancancer
(http://www.fda.gov) and is inadvanced clinical trials against anaplasticthyroid cancer, in combination with
paclitaxelandcarboplatin(http://www.clinicaltrials.gov).
10 TerrestrialPlantsasaSourceofNovelPharmaceuticalAgents
Thesynthesisofmanycombretastatinanalogues(e.g.,18a,18b,and18c)clearlyillustratesthepowerofa
relatively simple natural product structure to spawn a prolific output of medicinal and combinatorial chem-
istry.36,38,39 Most synthetic congeners contained the essential trimethoxy aryl moiety linked to substituted
aromaticmoietiesthroughavarietyoftwoorthreeatombridgesincludingheterocyclicringsandsulfonamides.
Anumberofcombretastatinmimicsarebeingdevelopedandthreeanaloguesareinclinicaltrials40while11are
inpreclinicaldevelopmentaspotentialanticanceragents.
2.02.3.5 Homoharringtonine
Homoharringtonine(HHT)(19)isanesterderivativeoftheparentalkaloidcephalotaxine(20),whichhasan
unusual tetracyclic ring system. Cephalotaxine was isolated from two Cephalotaxus species41 and its final
structure was assigned by X-ray crystallography.42 HHT was isolated in 1970 by workers at the USDA
laboratoriesinPeoria43butitsanticanceractivitywasfirstrecognizedbyChineseinvestigators.
HHTfunctionsasaninhibitorofproteinsynthesisandthisappearstobeitsmajormechanismofaction.Itis
active against several murine tumors, including L1210 and P388 leukemias and B26 melanoma, and it was
selectedfordevelopmentbecauseofitsactivityanditsrelativelyhigheravailabilityinplants.Ithasadvancedto
severalPhaseIIclinicalstudiesbutithasnotyetbeenapprovedforclinicaluseintheUnitedStatesorEurope.
Itssynthesis,medicinalchemistry,andmechanismofactionhavebeenreviewed.44Itsclinicaldevelopmentand
use have also been reviewed.45 The latter review concludes, ‘‘However, the promising activity of HHT in
patients with CML, MDS, APL, central nervous system leukemia, and polycythemia vera, as well as the
developmentofpuresemisyntheticHHTandHHTderivatives,shouldreinvigorateresearchtoestablishthe
valueofHHTinhematologicmalignanciesaswellasothertumors.’’45
2.02.3.6 TaxolandItsAnalogues
Thediterpenoid21wasisolatedfromthebarkofthewesternyew,TaxusbrevifoliaNutt,inthelate1960sby
MonroeWallandMansukhWaniaspartofasystematicsearchforanticancercompoundsfromplantsources,