S -Camptothecin

The protected E-ring moiety of (S)-camptothecin has been prepared in enantio-merically enriched form by the enzymatic resolution of a triester with PLE in a pH 7 phosphate buffer-acetonitrile (5 1) solution (Figure 6.7). The alkaloid camptothecin is an inhibitor of the enzyme topoisomerase and some of its derivatives are anticancer drugs [52]. 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Kirichenko AV, Rich TA, Newman RA, Travis EL. Potentiation of murine MCa-4 carcinoma radioresponse by 9-amino-20(S)-camptothecin. Cancer Res 1997 57(10) 1929-1933. 

Kirichenko AV, Mason K, Straume M, Teates CD, Rich TA. Nuclear scintigraphic assessment of intestinal dysfunction after combined treatment with 9-amino-20(S)-camptothecin (9-AC) and irradiation. Int JRadiat Oncol Biol Phys 2000 47(4) 1043-1049. 

During the course of clinical development, it is often important to identify the structures of metabolites. This information provides an opportunity to better understand interpatient variability in pharmacokinetics and toxicity. Clinical studies performed by Lokiec and coworkers, 1996 on a semisynthetic derivative of 20(S)-camptothecin, CPT-11, demonstrate the use of LC/MS to investigate the in vivo metabolic pathways. CPT-11 is a potent inhibitor of topoisomerase II, which is an enzyme involved in DNA duplication, and exhibits significant activity against various types of tumors in clinical studies. The understanding and control of the main biotransformation pathways are particularly important for anticancer drugs because therapeutic doses are often close to the maximum tolerated dose. 

Verschraegen, C. F, Gilbert, B. E., Loyer, E., Huaringa, A., Walsh, G., Newman, R. A., et al. (2004), Clinical evaluation of the delivery and safety of aerosolized liposomal 9-nitro-20(s)-camptothecin in patients with advanced pulmonary malignancies, Clin. Cancer Res., 10, 2319-2326. 

Bhatt [3] prepared antineoplastic agents consisting of poly-L-glutamic acid— camptothecin conjugates, (III) and (IV), as a method for improving the limited solubility of 20(S)-camptothecin and analogues in aqueous medium. 

An excellent example of vinylic substitution in the formation of a five-membered ring by an intramolecular Heck reaction is found in Comins and co-workers remarkably short synthesis of camptothecin (30) [six steps to ( )-camptothecin [7] and ten steps to (S)-camptothecin [8]. In the enantioselective synthesis, intermediate 29, which is obtained from /V-alkylation of the corresponding pyridone with a bromomethyl-bromoquinoline inteimediate, undergoes Heck closure to provide (5)-camptothecin (30) in 59% yield (Scheme 6-5). From a strategic standpoint, use of the Heck cyclization achieves excellent convergency as the central C-ring is formed late in the synthesis after combining two... 

A practical six-step synthesis of (S)-camptothecin was developed by D.L. Comins and co-workers." In order to prepare the DE ring fragment, 2-methoxypyridine was Iithiated at C3 with mesityllithium and treated with A/-formyl-A/,A/, A/ -trimethyl ethylenediamine to form an -amino alkoxide in situ. In the same pot, the addition of n-BuLi brought about a directed lithiation at C4 to afford a dianion, which was trapped with iodine and treated with NaBHVCeCIs to give the desired 4-iodo-2-methoxy-3-hydroxymethyl pyridine in 46% yield. 

Sawada, S., Yaegashi, T., Furuta, T., Yokokura, T., Miyasaka, T. Chemical modification of an antitumor alkaloid, 20(S)-camptothecin E-lactone ring modified water-soluble derivatives of 7-ethylcamp-tothecin. Chem. Pharm. Bull. 1993, 41, 310-313. 

Heck cyclization 4 A short, efficient, and asymmetric synthesis of the anticanccr alkaloid (S)-camptothecin (4) involves N-alkylation of the optically active hydroxylactone 1 with the bromoquinolinc 2 to provide 3. This product undergoes Heck cyclization to the alkaloid 4 in 59% yield. 

Intermolecular radical bond formations with companally high yields and stereoselectivities are still very rare in the total synthesis of bioactive compounds. One exception is Curran s camptothecin synthesis. However, progress in acyclic stereoselection of radical reactions [11] should soon help to formulate new solutions for these synthetic challenges. 

Initial reports on quinolyl and isoquinolyl radicals were first published in the 1970s (75JA1548, 73JA6863, 72JOC3199), but their use in the synthesis of heterocycles was first reported by Comins (94TL5331), where the synthesis of (S)-camptothecin 206 is described. The radical step takes place in the construction of the C ring (Scheme 54). 

An enolate conjugate addition to a p-bromomethacrylate offers a good route to the protected E-ring fragment of (S)-camptothecin, a 6-oxodihydropyran-3-carboxylic acid 28 <01JCS(P1)2903>. 

Other methods of esterification that do not utilize a carbodi-imide coupling method have also been explored. For example, the stereoselective esterification of 20-(S)-camptothecin, a hindered 3 ° alcohol, with amino acid derivatives was accomplished with the use of scandium triflate (Sc(OTf)3) in high yields while retaining the integrity of the amino acid stereocenter (eq 9). ... 

Scheme 13.33 Bond-sets of Danishefsky s and Curran s camptothecin synthesis...

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