Camptothecin antitumor activity

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

Fan Y, Shi LM, Kohn KW, Pommier Y, Weinstein JN. Quantitative structure-antitumor activity relationships of camptothecin analogues cluster analysis and genetic algorithm-based studies. J Med Chem 2001 44 3254-63. 

Kawato Y, Furuta T, Aonuma M et al. Antitumor activity of a camptothecin derivative, CPT-11, against human tumor xenografts in nude mice. Cancer Chemother Pharmacol 1991 28 192-198. 

Das has described the cycloaddition of camptothecin (92), an alkaloid with potent antitumor activity, with maleic anhydride under the action of microwave irradiation in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and 94, were produced. The first was formed by involvement of the B-ring in a hetero Diels-Alder reaction whereas the second was formed by involvement of the C-ring, probably through Diels-Alder reaction of intermediate 95 (Scheme 9.28). 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

Kunimoto T, Nitta K, Tanaka T, et al. Antitumor activity of 7-ethyl-10-[4-(l-piperidino)-l-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, againstmurine tumors. Cancer Res 1987 47(22) 5944-5947. 

Bernacki RJ, Pera P, Gambacorta P, Brun Y, Greco WR. In vitro antitumor activity of 9-nitro-camptothecin as a single agent and in combination with other antitumor drugs. Ann N YAcad Sci 2000 922 293-297. 

Greenwald, R. B., A. Pendri, C D. Conover, Y. H. Choe, C. W. Gilbert, A. Martinez, J. Xia, H. Wu, andM. Hsue. 1998. Camptothecin-20-PEG ester transport forms the effect of spacer group on antitumor activity. Biorg. Med. Chem6 551-562. 

The antitumor activity displayed by camptothecin (28) and its analogues has led to a great deal of interest in such compounds.36 Camptothecin is a complicated alkaloid to isolate, and analogues, which are of biological interest, are synthesized from the natural product itself.37 This need to access a wide range of analogues has led to a need for synthetic studies directed toward the development of a concise, yet inexpensive, total synthesis of camptothecin. 

Camptothecin (1) was first isolated in 1966 from the Chinese tree camptotheca acuminata [1]. As shown in Fig. 1, the five rings of the natural compound are named A, B, C, D and E. The stereo-genic center in the E ring is 5-configured. The antitumor activity of camptothecin quickly made the compound an interesting target for synthetic chemists. After a short time, successful total syntheses were reported. Especially three synthetic approaches should be mentioned here ... 

Camptothecin was discovered during a program of screening plant extracts for antitumor activity, launched by NCI in 1955. The unusual activity of the extracts of Camptotheca acuminata against some leukemia cellular lines prompted a study of the... 

Fig. 16.2 Structure-activity relationships for antitumor activity in camptothecins as known around 1995.

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

Camptothecin (43) was first isolated by Monroe Wall and Mansukh Wani in 1966, after ethanolic extracts of Camptotheca acuminata, a tree native to China, showed unusual and potent antitumor activity (63). Starting with 19 kg of dried wood and bark. Wall and Wani painstakingly purified the principal active component with a combination of hot solvent extraction, an 11-stage Craig countercurrent partition process, silica gel chromatography, and crystallization. Camptothecin was characterized as a novel pentacyclicalkaloid, present as j ust 0.01 % w/w of the stem bark of C ax umi-... 

Jaxel, C Kohn, K. W Wani, M. C Wall, M. E and Pommier, Y. (1989) Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I evidence for a specific receptor site and a relation to antitumor activity. Cancer Res. 49,1465-1469. 

Finally, it may be worthwhile to point out that one of the most successful chemotherapeutic drugs provided by nature may be considered as a non-classical active-site-directed irreversible inhibitor This drug is penicillin (70). As a non-classical antimetabolite of D-alanyl-D-alanine, it first forms a reversible complex with the enzyme peptidoglycan transpeptidase, and then by a ringopening reaction of its p-lactam moiety, it forms a covalently linked penicil-loyl-enzyme complex97. However, the reaction involves the acylation of a sulfhydryl group in the active site of the enzyme in this respect, 70 resembles the classical-type endoalkylating antimetabolites, azaserine and DON (8 and 9, see Section 2.2.). Some of the more recently discovered antibiotics and natural products from plants with antitumor activity (e.g., camptothecin) are... 

Caiolfa VR, Zamai M, Fiorino A, et al. Polymer bound camptothecin initial biodistribution and antitumor activity studies. J Control Release 2000 65 105-119. 

The camptothecins were discovered in extracts from the Chinese tree Camptotheca acuminata. Initial studies showed that camptothecins had antitumor activity, but clinical trials demonstrated severe side effects and toxicity. Numerous camptothecin analogues have been synthesized several have received FDA approval (irinotecan and topotecan), whereas others are still in clinical trials. 

Camptothecin, a plant alkaloid derived from Camptotheca acuminata, is a potent inhibitor of DNA topoisomerase I. Clinical trials failed to show expected antitumor activity, and the drug produced severe, unpredictable toxicity. The camptothecin analogs irinotecan and topotecan were synthesized to reduce toxicity and improve therapeutic... 

Kingsbury, W.D., Boehm, J.C., Jakas, D.R., et al. (1991) Synthesis of water-soluble (aminoalkyl)camptothecin analogues inhibition of topoisomeiase I and antitumor activity. J. Med. Chem. 34 98-107. 

The parent camptothecin alkaloid, isolated from bark of Camptotheca acuminate, has antitumor activity, but its limited water solubility necessitated delivery as ... 

Gallo RC, Whang-Peng J, Adamson RH. Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Natl Cancer Inst 1971 46 789-795. 

It was shown that camptothecin inhibits DNA and RNA synthesis at a concentration of Smmol/l by using HeLa and LI 210 cell lines. It shows inhibitory activity against a number of tumor cell lines and possesses a wide spectrum of antitumor activity [5]. Clinically it has side effects, such as disorder of the bone marrow, disorder of the digestive system such as nausea, vomiting, and diarrhea, and a decrease in white blood cells. Consequently it... 

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