7-ethyl-camptothecin

Rivory LP, Bowles MR, Robert J et al. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 1996 52 1103-1111. 

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. 

Examples of GDEPT include irinotecan (CPT-11), a prodrug of 7-ethyl- 10-hydroxy-camptothecin activated by carboxylesterase 5-fluorocytosine, a prodrug of 5-FU activated by cytosine deaminase and cyclophosphamide, a prodrug of 4-hydroxycyclophosphamide activated by cytochrome P450, which degrades into acrolein and phospho-ramide mustard.112-115... 

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. 

The camptothecin synthesis of Shen/Dani-shefsky [16] (Scheme 8) starts with the construction of the D ring reaction of 46 with 47 affords 48. The next step (48 49) introduces the C20 ethyl group. Hydroxymethylation of 49 delivers lactone SO. The B ring of the camptothecin precursor 52 should be accomplished by a Friedlander condensation of 10 with 11. For this purpose, a keto group at C2 of the C,D,E ring building block had to be installed. Shen and Danishefsky solved this problem by combination of an aldol condensation (50 —> 51) and a subsequent ozonolysis (51 11). Important for... 

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). 

In contrast to the structurally related topotecan, irinotecan is a prodrug, which has to be converted to its active form, SN-38 (4,30). Cleavage of the side-chain, a bulky piperidino moiety, at the CIO position is rapidly catalysed by carboxylesterases after intravenous administration. SN-38 (7-ethyl-lO-hydroxy-camptothecin) is 1000 times more potent than the parent compound. There is an equilibrium between the active lactone and the inactive carboxylated forms in a pH- and protein-dependent manner for both irinotecan and SN-38 (31,32). 

Camptothecin is one of the bioactive components isolated from the fruits and leaves of Camptotheca acuminata Decne in China. Also camptothecin has anti-cancer effects.2 7-Ethyl- 10-hydroxycamptothecin (EHC), a camptothecin derivative, has stronger anti-cancer effects and weaker side-effects than camptothecin,3 however, its interaction mechanism with protein is poorly understood. 

As well as the syntheses " of isocamptothecin, an unnatural isomer having ring E laterally transposed, and compounds having camptothecin part structures, yet two more formal total syntheses (bringing the total so far to nine ), have been published in the year under review. Both syntheses produce de-ethyl-deoxycamptothecin (114b), which had previously " been converted into the alkaloid. 

Duan K, Zhang X et al (2010) Fabrication of cationic nanomicelle from chitosan-graft-polycaprolactone as the carrier of 7-ethyl-lO-hydroxy-camptothecin. Colloids Surf B 76 475 82... 

R.B. Kolhatkar, P. Swaan, H. Ghandehari, Potential oral delivery of 7-ethyl-lO-hydroxy-camptothecin (SN-38) using poly (amido-amine) dendrimers, Pharm. Res. 25 (7) (2008) 1723-1729. 

Although several enantioselective syntheses of camptothecin have been reported [66-69], there are some major limitations when considering a practical method for the preparation of the biologically active (205)-isomer. In 1987, the first asymmetric synthesis of (205)-camptothecin was reported by Ejima et al. [70]. They attempted an asymmetric alkylation of an indolizine derivative (18) Scheme 2.3) employing (/ )-tosylproline as a chiral auxiliary. Thus, ethylation of compound (18) with ethyl iodide in the presence of NaH [64% diastereo excess de)], followed by treatment with propanol pro-... 

An ethyl group at position 20 also appears to be specifically recognized by the enzyme-DNA complex, because no modifications of this group have increased activity. It should be noted that compound (37), in which the exocy-clic methylene group was expected to provide a more electrophilic alkylation target, exhibited potent camptothecin-like inhibition of Topo I activity [93]. 

Irinotecan [97682-44-55], antineoplastic, topoisomerase inhibitor, 142. The key intermediate 140 is prepared by phosgenation of 7-ethyl-lO-hydroxy-camptothecin 139 [101, 102],... 

Several enzymes can react with sterically hindered compounds. For example, the acetate of a tertiary alcohol can be hydrolyzed by papain in buffer-ethyl acetate (pH 6.5) with excellent -value (>400), affording the ( )-alcohol in 49% yield and 98% ee and the (S)-acetate in 50% yield and 99% ee. The remaining (S)-acetate was converted to 20(S)-camptothecin, which is a pentacyclic alkaloid with potent antitumor activity isolated from Camptotheca acuminata. The product ( )-acetate can be converted to the starting racemic acetate chemically in 70% yield (Fig. 10.22). 

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