Camptothecin derivatives

In a similar way (and as described for the aromatic isocyanides), aliphatic a, 3-un-saturated isocyanides can also be used, leading to similar structures with a cyclo-hexano instead of a benzo moiety [84]. Based on the approach using aromatic isocyanides, a small library of about 20 camptothecin derivatives has been prepared, of which irinotecan and topotecan have entered the clinical treatment of cancer [85]. For the synthesis of the camptothecin derivatives, 3-206 was alkylated with the appropriate propargylic bromides 3-207 to give 3-208, which were irradiated in benzene at 70 °C, together with the respective isocyanide 3-209 and hexamethylditin... 

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. 

Topotecan is the second camptothecin derivative it is itself an active drug, and received FDA approval as second line therapy in metastatic ovarian cancer (1996) and in SCLC (1998) [13], In addition, representatives of a second generation of topi inhibitors, the homocamptothecins, are now being developed for chemotherapy, e.g., BN-80915 and BN-809271 [14]. 

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). 

Sugiyama, Y., Kato, Y., and Chu, X. (1998) Multiplicity of bdiary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide role of canalicular multispecific organic anion transporter and P-glycoprotein. Cancer Chemother. Pharmacol. 42(suppl), S44-S49. 

OmuraM,TorigoeS,KubotaN. SN-38, ametabolite of the camptothecin derivative CPT-11, potentiates the cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids. Radiother Oncol 1997 43(2) 197-201. 

Chen AY, Okunieff P, Pommier Y, et al. Mammalian DNA topoisomerase I mediates the enhancement of radiation cytotoxicity by camptothecin derivatives. Cancer Res 1997 57 1529-1536. 

Some ring-substituted (hydroxy or methoxy) camptothecin derivatives were either isolated in nature or obtained synthetically [253,264-267]. The 9-methoxy- and 10-methoxycamptothecin are less active, but 10-hydroxy-camptothecin is more active than the parent alkaloid against leukaemia P388 [253, 264], Both camptothecin and its 10-hydroxy derivative are being used in mainland China for the treatment of liver carcinoma and tumours of the head... 

Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

Today, several soluble camptothecin derivatives such as topotecan (3), 9-aminocamptothe-cin (4) and irinotecan (CPT-11) (5) are of clinical importance. Positive results were achieved, especially against intestinal, breast and ovarian can-... 

Scheme 16.7 Minisci reactions in the semisynthesis of camptothecin-derived drug candidates.

Rubin E, Wood V, Bharti A et al. A Phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin. Clin Cancer Res 1995 1 269-76. 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

The acute form of diarrhea is short-lived and can be effectively prevented or rapidly suppressed by concomitant atropine. The cholinergic symptoms are accompanied by abdominal cramps (36%), sweating (57%), salivation (11%), visual disturbances (15%), lacrimation (12%), and piloerection (3%). The recommended dose of atropine is 0.25 mg intravenously for prevention or 0.25-1.0 mg for acute treatment of patients with early cholinergic symptoms. As cholinergic symptoms have not been observed with other camptothecin derivatives, it can be speculated that these adverse effects are restricted to irinotecan, whose piperidino group bears some structural similarity to the potent nicotine receptor stimulant dimethylphenylpiperazinium (106). 

Minami H, Fuji H, Igarashi T, Itoh K, Tamanoi K, Oguma T, Sasaki Y. Phase I and pharmacological study of a new camptothecin derivative, exatecan mesylate (DX-8951f), infused over 30 minutes every three weeks. Clin Cancer Res 2001 7(10) 3056-64. 

The silatecan (DB-67) (21) represents a new generation of camptothecin derivatives (see Table 12) that exhibits a potent in vitro DNA topoisomerase I (TOPl)-mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers [79]. This new agent was found to be 25-times more lipophilic than camptothecin it incorporates readily into cellular and liposomal bilayers. In addition, its 10-hydroxy functionality enhances drug stability in the presence of human serum albumin. Thus, the net... 

Median effective concentrations for inhibition of the proliferation of five glioma cell lines by a variety of camptothecin derivatives... 

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. 

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