Masamichi Sugimori

A New Water‐soluble Camptothecin Derivative, DX‐8951f, Exhibits Potent Antitumor Activity against Human Tumors in vitro and in vivo

CPT‐11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT‐11 is a pro‐drug that is converted to an active metabolite, SN‐38, in vivo by enzymes such as carboxylesterase. We synthesized a water‐soluble and non‐pro‐drug analog of camptothecin, DX‐8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti‐proliferative activity of DX‐8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN‐38 or SK&F 10486‐A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX‐8951f administered i.v. at 4‐day intervals against human gastric adenocarcinoma SC‐6 xenografts was greater than that of CPT‐11 or SK&F 10486‐A. Moreover, it overcame P‐glycoprotein‐mediated multi‐drug resistance. These data suggest that DX‐8951f has a high antitumor activity and is a potential therapeutic agent.

Asymmetric synthesis of (S)-camptothecin☆

The title compound was synthesized via a novel diastereoselective ethylation process from indolizine derivative 5a bearing N-tosyl-(R)-proline.

Novel resolution of the anthracyclinone intermediate by the use of (2r, 3r)-(+)- and (2s, 3s)-(-).1,4-bis(4-chlorobenzyloxy)butane-2,3-diol: a simple and efficient synthesis of optically pure 4-demethoxydaunomycinone and 4-demethoxyadriamycinone☆

Abstract (±)-7-Deoxy-4-demethoxydaunomycinone((±)-3) was found to be cleanly resolved by forming a mixture of the diastereomereic acetals((-)-9and(+)-10 or(+)-9 and(-)-10)with the title vicinal-diol(+)-or ( )-5), affording optically pure (R)-( )-3. The resolving agents (( + )- and ( )-5) were readily synthesized from unnatural(2S,3S)-(-)-tartaric acid((-)-6)or D-(-)-mannitol and natural (2R,3R)-(+)-tartaric acid((+)6), respectively. The undesired enantiomer ((S)-(+ )-3) obtained by the optical resolution could be racemized by heating with trifluoromethanesulfonic acid in aq acetic acid. Optically pure (R)-3 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-2b) and (+)-demethoxyadriamycinone ((+)-2a) by featuring highly stereoselective ( ⪢ 20:1) introduction of the OH group into the C7-position as a key step.

(+)- and (-)-1-0, 4-0-bis(p-chlorobenzyl)threitol as novel resolving agents for optically active anthracyclinone synthesis: an efficient synthesis of optically pure 4-demethoxydaunomycinone

(±)-7-Deoxy-4-demethoxydaunomycinone(±)-3) was cleanly resolved by forming a mixture of the diastereomeric acetals ((−)-9 and (+)-10 or (+)-9 and (−)-10 with the title vicinal-diol((+)- or (−)-5) to give optically pure (R)(−)-3. The method for racemizing the undesired enantiomer((S)(+)-3) was also explored. Optically pure (+)-4-demethoxydauno-mycinone ((+)-2b) was elaborated from (R)(-)-3 according to the reported reaction scheme.

Antitumor Agents. VI. Synthesis and Antitumor Activity of Ring A-, Ring B-, and Ring C-Modified Derivatives of Camptothecin

Eleven ring A-, ring B-, and ring C-modified analogues of the antitumor alkaloid camptothecin (1) were prepared and evaluated for cytotoxicity and antitumor activity against P388 mouse leukemia. Among the six ring A-modified analogues, hexacyclic compound (14) retained the same order of activity as (1). Most of the ring B- and ring C-modified analogues displayed greatly reduced activity, whereas compound (39), which has an alkylidene group at position 5, was found to be as active as (1). These results confirmed the necessity of the intact rings A, B, and C of (1) for antitumor activity. Further, the higher activity of (14) and (39) suggest that the «northern» part of the camptothecin molecule may be a suitable site for functionalization to obtain more potent analogues of (1)

Antitumour agents. Part 2. Asymmetric synthesis of (S)-camptothecin

The total synthesis of (S)-camptothecin by a novel diastereoselective ethylation process is described.

Stable keto-tautomer of tetrahydroxynaphthalene in alkali: Theoretical support to the post-aromatic reduction in the biosynthesis of aromatic polyketides

Abstract The structure of the most stable ionic species of 1,3,6,8-tetrahydroxynaphthalene in alkali was investigated by the semi-empirical (AM1) and ab initio (3-21+G//3-21G) molecular orbital calculations. It was concluded that the most stable species was a non-symmetrical ketotautomer trianion.