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Baran Group Meeting Reviewing Camptothecin Ke Chen9/ 26/ 2007 In Fig 1, normally, topoisomerases I introduces a nick in the DNA backbone allowing the rotation of one strand around another. This O releases the torsional strain which otherwise accumulates in front of N the advancing replication fork (the large arrow). The DNA break is extremely transient and is religated as it release the other strand. N O OH O Name Camptothecin IUPAC name 4-ethyl-4-hydroxy-1H-pyrano[3,4:6,7] indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione CAS number 7689-03-4 Formula C20H16N2O4 Mol. mass 348.352 g/mol This quinoline based alkaloid was found in the bark of the Chinese camptotheca tree. Camptotheca goes by many names in China, including "happy tree", Fig 1 Fig 2 "dragon tree" and "fine tree". Chinese have used the "happy tree" in traditional medicine for thousands In Fig 2, when camptothecin is present(black oval with C), it binds to the of years. It has been used for psoriasis, leukemia and diseases of liver, topoisomerase I-nicked DNA complex. This prevents the religation of the gallbladder, spleen, and stomach. nicked strand and the release of the enzyme. Eventually, the replication fork collides with the complex, causing the formation of a double-strand During the last half century, scientists have discovered its potential as a break. selective anticancer drug.The unique mode of action for this potent cytotoxic compound was found to Hsiang, Y.H. Cancer Res. 1989, 49, 5077.act via inhibition of an enzyme known as DNA topoisomerase I. 1
Baran Group Meeting Discovering Camptothecin Ke Chen9/ 26/ 2007 Monroe E. Wall (1916–2002) Timeline of Camptothecin: Born in 1916 in Newark, NJ, Dr. Wall received 1960-1966 Isolation of active compound from amptotheca acuminata; his B.S., M.S., and Ph.D. degrees from determination of structure of camptothecin Rutgers University. In 1941, he joined the United States Department of Agriculture. From 1941 to 1960, O O Dr. Wall gained national recognition as a N N OH government scientist in steroid chemistry. In N N 1960, Dr. Wall joined the Research Triangle Na+ Institute (RTI) to start a chemistry research O O group. He became RTI Vice President of Chemistry and Life Sciences in 1971. Among OH O OH O numerous contributions to the field of natural product research, he is best known for the discovery and development of taxol and low solubility in water water-soluable but inactive camptothecin. In 1981 He retired from administration and devoted his time to research Clinical trials started in the 1960s but were abandoned shortly thereafter. until two weeks before his death at 85. 1985 Determination of mechanism of action of camptothecin Monroe Doctrine: "Get good people, support them with good facilities, do good science, work hard, and keep doing it." After Camptothecin returned, like " the phoenix from the ashes", it rekindled interest in developing analogs of camptothecin that were both water soluble and retained anticancer activity Mansukh C. Wani 1996 FDA approval of two analogs of camptothecin for treatment Born in Nandurbar, India, Dr. Wani received of ovarian, lung, breast and colon cancer. his B.S. and M.S. degrees from the University of Bombay. He came to the United States and finished his Ph.D in chemistry at Indiana Some numbers and facts... University under the instruction of Professor Ernest Campaign. After a postdoctoral 11729 publications regarding "camptothecin". fellowship at the University of Wisconsin- Madison, he accepted a position at RTI from 114 publications involving total or formal synthese of camptothecin and its Dr. Wall in 1962. Together they developed two derivatives. of the most promising anticancer agents, taxol and camptothecin., which are By 2001, the analogs developed included Pharmacia’s Camptosar and benefiting millions of people all over the GlaxoSmithKline’s Hycamtin, collectively reporting worldwide sales world. Dr. Wani is still active at RTI, approaching $ 800 million. supervising junior researchers. Synthetic chemists embrace practility and perfection. 2
Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen9/ 26/ 2007Classical condensation O N O O O N N N CO2H Friedlander quinoline synthesis O N Ts CN O O CN O O Na2CO3, DMF, 70 oC CO2Et OH O CO2Et O O 76-97 % Br NH2 CO2Et aq. NaOH NTs N CO2Et CHO N 50 % N O CO2Et CO2H O N O N CN NaH, EtI, DMF O O steps O O rt, 65-100 % CO2Et O N O Et N OH O O NTs N NTol N O d. r. = 82 :18 NH2 Et CO2Et O 1 eq LDA Et CO2Et Et p-TsOH, tol O o CO2Et reflux, 73 % CO2Et -78 C O CO2Et LDA, RT 1. First asymmetric synthesis O N EtO2C 2. 1,4-Asymmetric induction in the diastereo- dl-camptothecin N Et CO2Et selective ethylation was achieved using an N-tosyl-(R)-proline derivative O OH 1. First synthesis reported OH O 2. One of the key steps involves the annulation of an ester carbonate and unsaturated lactam Tagawa H. Tetrahedron Lett. 1989, 30, 2639-2640. Stork G., Schultz A. G. J. Am. Chem. Soc. 1971, 36, 4074-4075. 3
Baran Group Meeting9/ 26/ 2007 Camptothecin: From Bench to Bedside Ke ChenClassical condensation CO2Me CO2Me 1. PhCHO, NaHMDS O O O 2. O3 O 3. TMSCHN2 O 1. quinine-water HO N O N O 2. recrystalization Et 85 % overall HO2C O O CO2H CO2H OH 3. MeOCOCl, Et3N NTol O N Et OCO2Me Cl Et OCO2Me NH2 1. HBr, 140 oC 1. O2, eosine N O O dl-CPT 2. SOCl2 O O p-TsOH, tol O 2. Me NH, CuCl MeO2C 2 2 O O reflux, 75 % O2, DMF pyr O O (S)-camptothecin N Danishefsky S. J. J. Org. Chem. 1993, 58, 611-617. NH Danishefsky S. J. J. Am. Chem. Soc. 1971, 93, 5575. Corey E. J. J. Org. Chem. 1975, 40, 140-2141. O O R2 (CH2O)n/H+ R2 O R2Friedlander quinoline synthesis CO2Me Et CO2Me N N O N R1 R1 R1 H H Et3N N • CO2Me O O O CO2Me CO2Me H MeO2C N major 92 % O Two analogs: CO2Me Et + CO2Me HO t-BuOK/EtI (CH2O)n/H O HO CO2Me O O N DME, 91 % N N 95 % N N O N O O O O OH O OH O 4
Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen9/ 26/ 2007 OModern organic chemistry Other recent applications of 1,4-addition to pyridinium salts N N O Me F N I- CO2Me LDA PhSeBr OH O ? N F N OTf intermediate CO2Me Me O DCM, rt N CO2Me 30 min N Br Me H SePh OTf Br N -30 oC Methylervitsine 1.5 h H O OLi N CO2Me LDA, THF Me O O O O O -78 oC, 30 mins Bennasar M. L.. J. Chem. Soc., Chem. Commun. 1995, 125. then DDQ O O N CO2Me Bn Bn N O N N N Br C6H11N=C O N Br AcONa, MeOH, 65 oC O NH2 O NC OH O 71 % C6H11 O N O H Bennasar M. L.. J. Chem. Soc., Chem. Commun. 2000, 2459. Lavilla R. Org. Lett 2006, 8, 5789-5792. Bennasar M. L.. J. Org. Chem. 2002, 67, 7465. 5
Baran Group Meeting Discovering Camptothecin Ke Chen9/ 26/ 2007Diels-Alder Reaction: MeO EtO OEt O MeO O OMe Me3OBF4 OMe N O N EtO N H reflux N CN OEt rt Ms OEt CN 82 % NSO2Me N OEt N N OEt CO2Et Revised alternative: CO2Et OEt OMe OMe O O 86 % ee N O Ac2O N OEt N N N OEt N N H reflux N CN OEt Modified CO2H OEt CN Sharpless 75 % Dihydroxylation HO OMe O OMe OAc O HO 1. HBr O N O N NaClO2 N OEt 2. K2CO3 O N N N N CN NaH2PO4 OEt O O N CN HO OH 48 % 74 % OH O O Boger, D. L.. Tetrahedron 2002, 58, 6343. Fortunak J. Tetrahedron Lett. 1996, 37, 5679-5682. 6
Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen9/ 26/ 2007[4+1] Radical Annulation: Curran and Shibasaki: CO2H O 1. PCl5 O 2. HBr N OMe HN OMe CN 3. MeOH CO2Me CO2Me Br 5 mol % SmLn N OTBS CO2H Br N OTBS Et 1.5 equiv TMSCN CN PhNC SMT SMT Me3SnSnMe3 EtCN, -40 oC, 18 h Et OTMS O 98 %, 84 % ee OMe O O N 1. ICl TMSI, cat H2O 2. HCl-EtOH N O CH3CN, 87 % HN O dl-Camptothecin N 71 % (2 steps) I O I O CO2Me Et OH Et OH Et > 99 % ee after Over 100 derivatives of camptothecin have been prepared by Dr. Currans recryst. from MeOH-CHCl3 research group utlizing this approach. O O PhNC O N N N N Br R R R O O N N N N Shibasaki M.; Curran D. P. J. Am. Chem. Soc. 2001, 123, 9908-9909. R CO2Me Shibasaki M. J. Am. Chem. Soc. 2000, 122, 7412-7413. Et Curran D. P. J. Am. Chem. Soc. 1992, 114, 5863-5864. 7
Baran Group Meeting Camptothecin: the Future Ke Chen9/ 26/ 2007 Structure-Activity Relationships: 1. MesLi N Li N 2. N NCHO 1. I2 2. NaBH4, H2O N OLi O N OMe A B C N one pot D HO 3. n-BuLi N OMe N O E O N I N I OH O O TMSCl, NaI 1. n-BuLi OH O (CH2O)n, CH3CN 2. O Hycamtin OH O N OMe N O CO2R* O O N Et Et OR* O N O HCl HO t-BuOK O LiO I N 10 additional CPT O iPrOH N Cl DME O derivatives in various N stages of clinical trials N O N O O H Camptosar OH O O O N N (Ph3P)2Pd(OAc)2 N N Cl O KOAc, CH3CN O "Trees hold the answer to saving the planet. Scientists are discovering more remarkable facts about trees, forests and animal interactions than ever before. OH O OH O The work of these scientists is immeasurably protecting humanity and all life, now and into the future."This remains the most efficient route reported (six steps, 12.5 % overall yield).Scientists from GSK are utilizing this approach to synthesize analogs of CPT. Reese Halter Comins D. L. Org. Lett 2001, 3, 4255-4257. 8