Chemistry And Biology Of Selected Natural Products
Pure&App/. Chem., Vol. 68, No. 11, pp. 2129-2136, 1996.Printed in Great Britain.0 1996 IUPACChemistry and biology of selected natural productsK. C. Nicolaou,* E. A. Theodorakis, C. F. ClaiborneDepartment of Chemistry, The Scripps Research Institute, 10666North Torrey PinesRoad, La Jolla, California 92037, and Department of Chemistryand Biochemistry,University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093Abstract: Natural products often offer excitement, stimulation, challenges and opportunities for chemists, biologists and medical investigators. The study of theirchemistry, biology and medicine provides, more often than not, rewards imagined andunimagined, and is still a major frontier in organic chemistry. In this article we summarize some of our recent work in this area and project ahead to the future of the field.IntroductionMan's fascination with natural products goes back to ancient times (1). With the discovery ofsalicin from willow tree extracts and the development of aspirin in 1899, the art of exploiting naturalproducts became a molecular science. The discovery of penicillin in 1928 and its subsequentdevelopment as a drug represents another milestone in the history of natural products, and markedthe beginning of a new chapter in drug discovery, in which bacteria were added to the plant kingdomas sources for biologically active substances. Today, with marine organisms and other livingcreatures as additional sources of active compounds, the chemistry and biology of natural productsrepresents a major path to drug discovery and development. Indeed a large portion of today'smajor drugs have their origins in nature. It is, therefore, not surprising that one of the most activeand rewarding frontiers in modern chemistry is the study of the chemistry and biology of naturalproducts.In our laboratories the study of the chemistry and biology of natural products focuses on thefollowing endeavors: (a) total synthesis; (b) molecular design of mimics or antagonists of the naturalproducts; (c) chemical synthesis of the designed molecules; (d) molecular recognition experiments;(e) biological investigations; and (f) redesign and fine-tuning of molecular structure. The selectionof the target molecules is of paramount importance and is based on criteria of novel architecture,important biological function and interesting mechanism of action. Thus, with the proper selection,one optimizes the opportunities for the discovery and development of new synthetic technologyand strategies, and for useful contributions to chemistry, biology and medicine.With this concept in mind, we highlight below a number of recent programs from ourlaboratories, which led to exciting developments within the area of chemistry and biology of naturalproducts.Calicheamicin 7,'Calicheamicin (Fig. 1) belongs to anew class of extremely active antitumoragents, collectively known as enediynes (2).Isolated from soil bacteria, the enediynes arethought to exert their biological activities bygenerating highly reactive diradical speciesMe-;&Me0Fig. 1. Structure of calicheamiciny,'2129
K. C. NICOLAOU eta12130that are capable of damaging DNA (3). Themolecular structure of calicheamicin y canlbeseen as composed of three parts: (a) the 10membered enediyne ring system which uponactivation generates radicals via a Bergmancyclization (Fig. 2) (4); (b) the oligosaccharidedomain which recognizes and binds to the minorgroove of DNA, thereby serving as a deliverysystem; and (c) the trisulfide moiety whichserves as the initiation point for the cascade ofreactions leading ultimately to the diradicalformation.Fig. 2. Mechanism of astion of callcheamlcln y,'Me-NiOMeMe-!&OHMe0calichearniciny,'Fig. 3. Total synthesis of calicheamicin y,1up to 1000 times morepotent than the naturalcompound) againsttumor cells ( 8 ) . Themechanism of action ofthis svnthetic material.believedtobethemostcytotoxic non-peptidicagent known, involvesapoptosis initiated bydouble-strand DNA cuts(Fig. 4). Using similarHO.FMoOHAOMeMe-!&Me00and challenging target fortotal synthesis. The first totalsynthesis of calicheamiciny11 was reported in 1992from these laboratories (Fig.3) ( 5 , 6 ) . Our convergentstrategyinvolvedconstruction of the two keyintermediates representingthe oligosaccharide andenediyne parts of themolecule, followed bycoupling and elaboration tothe target compound (5).-[ calicheamicin '& ]* Causes double strand DNA cutsInitiates apoptosis [cell death]-Most potent, non-peptidic,cytotoxic agent knownA : DNA markers (123 base-pair fragment)6 : Untreated MOLT-4 leukemia cellsc : DNA extracted from untreated M O L T 4 cellsD : MOLT4 cells treated with calicheamicin yqlE : DNA extracted from [D]F: MOLT4 cells treated with calicheamicin 8,'0 : DNA extracted from IF]Fig. 4. Profile of designed calicheamicin 0?10 1996 IUPAC, Pure and Applied Chemistry68 2129-2136
Chemistryand biolow of natural products2131RapamycinOne of the most significant advances of modern medicineis the advent of organ transplantation. This revolution inmedicine was made possible with the use ofimmunosuppressive agents such as cyclosporin, FK506 andrapamycin (Fig. 5) (9). Although the story of this fascinatingmolecule commences with its isolation in the early 1970s (lo),it did not attract serious attention from the scientific communityuntil the 1980's, when the powerful immunosuppressiveproperties of cyclosporin and FK506 were discovered.Rapamycin's striking resemblance to the structure ofFK506 moved it to the forefront of chemical andbiomedical research as a challenging synthetic target,as a probe for immunological studies, and as a potentialdrug candidate in organ transplant operations.Rapamycin suppresses the immune system (blocks Tcell proliferation) by sequentially binding to two differentFKBP12proteins (11). It initially forms a complex with FKBP12which then proceeds to bind FRAP (orTOR, or RAFTl),a protein essential for the proliferation of T/ Y M 0cells, thus preventing it from carrying outits biological functions (Fig. 6).The challenging structure andpotential importance of rapamycin inmedicine provided a strong impetus forthedevelopment of a total synthesis and offeredample opportunityfor development of new:1f4e 0H.M.besynthetic technology and strategies.Fig. 7. Total svnthesis of rapamvcinAmong them is the double Stille couplingreaction ("stitching cyclization")featured in our total synthesis (12),which was used to constructsimultaneously the conjugated. .triene and macrocyclic ringsystems of the molecule (Fig. 7).OThreeother total syntheses of'OHRAP rapamycin have followed (12,13).In order to probe theRapamycin-Binds only to FKBP12*No immunosuppressiveeffectsstructure-activity relationshipsandFig. 8. Profile of designed RAP-PaITaxolTMThe modern history of TaxolTM(Fig. 9) began in the early1960s when A. Barclay, a botanist from the United StatesDepartment of Agriculture (USDA), collected samples of thePacific Yew tree (Taxus brevifolia) from a forest in WashingtonState as part of a major initiative to search for natural sources@J 1996 IUPAC,Pure and Applied Chemistry68.212%2136BzNH 0HOFig. 9.Ez6 &OfTaxolTM
K. C. NiCOLAOU era/.2132of anticancer agents (15). His samples foundtheir way, after initial biological screening, to thelaboratories of M. C. Wani and M. Wall, twochemists who isolated and determined itscytotoxic properties and elucidated its chemicalstructure with the help of X-raycrystallographers P. Coggen and A. T. McPhail(1 6). Taxol'sTMdevelopment was at first slow,until its unique mode of action was determinedby S. B. Horwitz and her group (17). This groupreported that TaxolTM binds to microtubulescausing their stabilization and thus preventingcell mitosis. Since the microtubules are themain components of the mitotic spindle which*cell forms disorganizedasters of microtubules*cycle stops at G W r o*cell deathFig. 10. Mechanism of action of TaxolTMmust smoothly separate into two new mitoticspindles during mitosis, Taxol'sTMbinding inhibitsthis process and thus kills the cells at the G2phase (prior to mitosis) (Fig. lO)(l8).Alerted to the great promise of TaxolTMandits derivatives and the initially short naturalFunctionalizationssupplies of the drug, we launched a program* Deprotectionsdirected towards its total synthesis. The syntheticstrategy developed in these laboratories relied ona convergent approach, whereby two fragmentsrepresenting rings A and C were constructed,each via a Diels-Alder reaction (19). Thesefragmentswere then joined together through aFig. 11. Total synthesis of T a x o PShapiro reaction and the elaborated product wascyclized using a McMurry coupling reaction to produce,after appropriate functionalizations, attachment of theside chain, and deprotections, TaxolTMin its naturallyoccurring form (Fig. 11)(19,20).Among the many taxoid analogs that weresynthesized in our laboratories, a water soluble protaxol*releases TaroiTMin vivo-promising anticancer activitywith a 2methylpyridinium group at the 2' position (2'MPA, Fig. 12) proved to be a highly promising Fig. 12. Profile of water-soluble protaxolcomDound as a Dotentiallv .imDroved form of TaxolTM(21). This latter compound is currently under investigation as a new anticancer agent.-1BalanolThe recent isolation and structural elucidation of balanol(Fig. 13) (22),represents a significant advance in the quest foreffective inhibitors of protein kinase C (PKC). PKC mediatedsignal transduction is known to lead to a variety of cellularresponses, including gene expression and cell proliferation (23),and activated PKC (when bound to ATP) has been implicatedHOHin diverse diseases such as cancer, cardiovascular disorders,Fia. 13. Structure of balanolasthma, inflammation, diabetes, and HIV infection (24).The biological mode of action of balanol is thought to involve competitive binding againstATP at the catalytic domain of PKC, thus inhibiting protein phosphorylation and signal propagationQ 1996 IUPAC, Pure andAppliedChemistr/B8.2129-2136
Chembtry and biology of natural productsProteinDiacylglycerol orKinase C Tumor Promoter(PW0inactive* Eactiven-2133ATPPADHHFig. 14. Mechanism of action of balanolFig. 15. Total synthesis of balanol(Fig. 14) (25). Consequently, the identification of potentand selective PKC inhibitors may not only serve to furtherilluminate the mechanism of signal transduction, but mayalso result in the development of novel drugs withconsiderable therapeutic value.Due to the biomedical importance of this molecule,we initiated a program directed towards the synthesis notonly of the natural balanol, but also of several designedanalogs. Our strategy (26), involved coupling of the twocomponents shown in Fig. 15, which after functional groupdeprotectiondelivered balanol in enantiomerically pure form(26,27). A combination of molecular design, total synthesisZaragozic Acid A (Squalestatin S1)The fascinating story of zaragozic acidA (squalestatin S1) (Fig. 17) commencedin 1992 with its isolationand characterizationindependently by two different companies:Merck (29) and Glaxo (30). The chemistryand biology o''arago'icacidA(squa'estatin0Acetvl Co-A[CholesterolNH'OH* Highly selective inhibitor of PKA*Potential anticancer aqentFig. 16. Proflle of 10"-deoxybalanolFlg. 17. structure ofzaragozlc a d d A (squalestatin SI)to presqualene pyrophosphate. Zaragozic acidA interferes at this point by inhibiting the actionof saualene svnthase. the enzvme that isresponsible for this transformation (Fig. 18). Inaddition, this remarkable compound exhibitspotent antifunqal activity and is an inhibitor ofras-famesyl tinsferase, which is implicated incarcinogenesis.Zaragozic acid A contains a highlyoxygenated and unique bicyclic core with threecarboxylic acid groups extending from it. Its totalwop,. . .FamesvI woDhoSDhateSynfhaseI,OH-- A,.A,.-.A .,".,m-,1 sz-vPresqualene pyrophosphete0 1996 IUPAC. PureandAppliedChemistry0a.2129-2136
2134K. C. NICOIAOU eta1synthesis presented an unusualchallenge and provided anopportunityto develop new syntheticstrategies (32,33). Our convergentsynthetic approach began withachiral precursors and involved theconstruction, coupling andelaboration of the three fragmentsshown in Fig. 19. Instrumental tothe success of this synthesis werea Sharpless asymmetric dihydroxylation reaction and a novel acidcatalyzed rearrangement of aspiro[3.9]bicyclo[4.3.0]nonanesystem to the [3.2.1]bicyclic,.Me Mn-FunctlonallzatlonsFig. 19. Total synthesis of zaragozic acid Askeleton of zaragozic acid A (32).A number of designed zaragozic acid analogs have alsoM ?ebeen synthesized and are currently under biologicalinvestigation,whileothersare underconstruction(Fig. 20) (34).MeMe "HOzC zCMeIt shouldabe mentionedat this juncturethat, in view of toxicityeffects,thenaturallyoccurringcompound(like many othernYCO,Hlead compounds) may not reach the clinic and thereforeFig. 20. Designed zaragozic acidsynthetic or semisynthetic mimics assume high priority asanalogpotential drug candidates in this area. Such molecules mayalso play important roles as biological tools.IIBrevetoxin BThe brevetoxins are a familyCHCof marine neurotoxins associatedwith the "red tide" occurences (35).These phenomena occur periodically around the world and areresponsiblefor catastrophickillingsof fish and other marine life as wellHHHLMeas human poisoning, throughFlg. 21. Slructure oi brevetoxln Bcontaminated food consumDtion.Within this family, brevetoxin B (Fig. 21), occupies a prominent position, as it was the first member tobe discovered. Its highly complex structure, reported in 1981 (36), represented at the time anunprecedented molecular architecture, consisting of a series of eleven trans-fused ether rings.The biological mode of action of brevetoxin B involves binding and activation of sodium channels(Fig. 22) (37). By virtue of its length (30 A) andhydrophobic properties, this molecule is able to enterthe cell membrane and bind to the sodium channels,thus changing their conformation. This allows aninflux of sodium ions, resulting in several unpleasantneurological and physiological effects and evendeath by asphyxiation (38).The unique structure of brevetoxin B together withits interesting biological activity and harmfulenvironmental consequences, prompted us to initiatea program directed towards its total synthesis.Towards the achievement of this goal, we had toI0 1996 IUPAC. Pure and Applied Chemisfry68.2129-2136
Chemistry and biology of natural productsOTPSFunctionalizationsbrevetoxin BFig. 23. Total synthesis of brevetoxin B2135develop a number of newsynthetic reactions andmethodsfortheconstruction of cyclicethers, thereby expandingthe collection of tools fororganic synthesis. In oursuccessful final strategy,two large segmentsrepresentingringsABCDEFG and IJK weresynthesized and coupledtogether, to produce, aftercycli-zation and finalfunctionalizations, thenatural product in its proper enantiomeric form(Fig. 23) (39).The developed methodology allowed thesynthesis of designed analogs of brevetoxin 6 . Ashorter analog, named truncated brevetoxin B[AFGHIJK] (Fig. 24), was synthesized (40) in orderto test the hypothesis put forward by Baden and 0HHMeGawley regarding the relationship between theto sodium channelsDevoid of ichthyotoxicityrequired length of the molecule and the binding toits receptor (37). The biological tests with the Fig. 24. Profile of truncated brevetoxin B [AFGHIJK]synthetic molecule supported this hypothesis bynot exhibiting significant binding to the sodium channel (41). Continued studies in this area areexpected to advance our knowledge of the structure and function of ion channels and to makesignificant contributions to neurobiology in general.1IConclusionIn this article, a number of projects in the authors laboratories involvingstudies in the chemistryand biology of natural and designed molecules have been briefly discussed. In all these projects,synthetic chemistry has played a major role, not only in synthesizing the natural compounds, butalso in rendering available synthetic molecules whose biological properties were investigated.While a number of these molecules are assisting investigations to probe biological issues, othersbecame drug candidates. The future of the science that blends chemistry and biology of naturalproducts looks, indeed, very exciting. With the increasing power of chemical synthesis, theprospects of discovery and invention of new chemical entities and new phenomena appear greaterthan ever. Chemists are destined to play a major role in this rapidly moving frontier. They shouldnot, however, forget that ground-breaking organic synthesis should also be practiced for its ownsake, for new advances in the latter field are still needed.Acknowlegdment. We would like to express our gratitude and appreciation to all our coworkers, whose names appear in the references, for their contributions to the research describedin this article. Our programs have been financially supported by the National Institutes of Health,Merck, Sharp and Dohme, Glaxo, Inc., Schering Plough, Pfizer, Hoffman La Roche, and the ALSAMFoundation.References1. J. Mann, Murder, Magic and Medicine, Oxford University Press, 1994.2. K. C. Nicolaou andW.-M. Dai,Angew. Chem. Ini. Ed. Engl. 30,1387 (1991).3. M. D. Lee, et al,J.Am. Chem. SOC.109,3464 (1987). M. D. Lee,et a1.J. Am. Chem.SOC.109,3466 (1987).0 1996 IUPAC, Pure and Applied Chemistry 68,2129-2136
2136K. C. NICOLAOU eta/.4. R. R. jones and R. G. Bergmann, J. Am. Chem. SOC.94,660 (1972). T. P. Lockhart and R. G. Bergman, J. Am. Chem. SOC.103,4091 (1981).5 . K. C. Nicolaou, C. W. Hummel, E. N. Pitsinos, M. Nakada, A. L. Smith, K. Shibayama and H. Saimoto, J. Am. Chem.SOC.114, 10082 (1992).6. For another synthesis see: S. A. Hitchcock, S. H. Boyer, M. Y. Chu-Moyer, S. H. Olson and S. J. Danishefsky, Angew.Chem Int. Ed. Engl. 33,858 (1994).7. K. C. Nicolaou, W.-M. Dai, S.-C. Tsay, V. A. Estevez and W. Wrasidlo, Science 256, 1172 (1992).8. K. C. Nicolaou, T. Li, M. Nakada, C. W. Hummel, A. Hiatt and W. Wrasidlo, Angew. Chem Int. Ed. Engl, 33, 183 (1994).9. M. K. Rosen and S. L. Schreiber, Angew. Chem. Int. Ed. Engl. 31,384 (1992).10. D. C. N. Swindells, F? S. White and F. A. Findlay, Can. J. Chem. 56, 2491 (1978). J. A. Findlay and L. Radics, Can. J.Chem. 58,579 (1980).1 I . S. H. Snyder and D. M. Sabatini, Nature Medicine 1, 32 (1995).12. K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa and P. Bertinato, J. Am. Chem. SOC.115,4419 (1993).13. For other syntheses see: D. Romo, S. D. Meyer, D. D. Johnson and S. L. Schreiber, J. Am. Chem. SOC.115,7906 (1993).C. M. Hayward, D. Yohannes and S. J. Danishefsky, J. Am. Chem. SOC.115,9345 (1993). A. B. Smith 111, S. M. Condon, J.A. McCauley, J. L. Leaser Jr., J. W. Leahy and R. E. Maleczka Jr, J. Am. Chem. SOC.117,5407 (1995).14. T. K. Chakraborty, H. P. Weber and K. C. Nicolaou, Chemistry & Biology 2, 157 (1995).15. T. Junod, Life 15,71 (1992).16. M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggen and A. T. McPhail, J. Am. Chem SOC.93,2325 (1971).17. S. B. Horwitz, J. Fant and P. B. Schiff, Nature 277, 665 (1979). E. Nogales, S. G. Wolf, I. A. Khan, R. F. Luduena, et al.Nature, 375,424 (1995).18. K. C. Nicolaou, W.-M. Dai and R. K. Guy, Angew. Chem. Int. Ed. Engl. 33, 15 (1994).19. K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. B. Renaud, E. A.Couladouros, K. Paulvannan and E. J. Sorensen,Nature 367,630 (1994).20. For another synthesis see: R. A. Holton, et al, J. Am. Chem. SOC.116, 1597 (1994). R. A. Holton, et al, J. Am. Chem. SOC.116, 1599 (1994).21. K. C. Nicolaou, R. K. Guy, E. N. Pitsinos and W. Wrasidlo, Angew. Chem. Int. Ed. Engl. 33, 1583 (1994).22. P. Kulanthaivel, et al, J. Am. Chem SOC.115,6452 (1993).23. Y. Nishizuka, Science 258,607 (1992).24. D. Bradshaw, C. H. Hill, J. S. Nixon and S. E. Wilkinson, Agents Actions 38, 135 (1993).25. A. Ohshima, M. Yanagisawa, A. Katoh, T
and rewarding frontiers in modern chemistry is the study of the chemistry and biology of natural products. In our laboratories the study of the chemistry and biology of natural products focuses on the following endeavors: (a) total synthesis; (b) molecular design
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