Hirofumi Terasawa

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.

New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetals. Part 4

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.

Orally active docetaxel analogue: Synthesis of 10-deoxy-10-C-morpholinoethyl docetaxel analogues

To improve cytotoxicity of 10-deoxy-10-C-morpholinoethyl docetaxel analogues against various tumor cell lines including resistant cells expressing P-glycoprotein (P-gp), we modified the 7-hydroxyl group to hydrophobic groups (methoxy, deoxy, 6,7-olefin, alpha-F, 7-beta-8-beta-methano, fluoromethoxy). Among these analogues, the 7-methoxy analogue showed the strongest cytotoxicity. This analogue showed potent activity against B16 melanoma BL6 in vivo by oral administration.

2 Recent Advances in the Medicinal Chemistry and Pharmacology of Camptothecin

Publisher Summary This chapter discusses recent advances in the medicinal chemistry and pharmacology of camptothecin. The discovery of new agents with novel mechanisms of action is the result of continual progress in the search for efficacious drugs for use in cancer chemotherapy. Although, the rate of successful outcomes of chemotherapy is not yet satisfactory, especially in the treatment of malignant solid tumours, the discovery of epoch-making agents, such as doxorubicin (adriamycin) and cisplatin, has improved the clinical efficacy of chemotherapy. It has taken almost three decades for camptothecin to be recognized as a major cancer chemotherapeutic agent. Camptothecin was first isolated from camptotheca acuminata decne (nyssaceae), which has been used for many years as a traditional Chinese medicine. Extensive studies of the natural distribution of this unique alkaloid led to its isolation from several plant families: Nothapodytes foetida , Ophiorrhizam ungos , Ervatmia heyneana , Merrilliodendron megacarpum , and Ophiorrhiza pumila . As the initial isolation and structure determination of camptothecin in 1966, numerous studies of the synthesis of analogues of this potent alkaloid have been carried out in order to define structure–activity relationships.

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.

Studies on the syntheses of heterocyclic compounds. Part 766. A total stereoselective synthesis of emetine and (±)-dihydroprotoemetine

Reaction of 3,4-dihydro-6,7-dimethoxy-1 -methylisoquinoline (3) with diethyl αγ-diethoxycarbonylglutaconate (2) in ethanol, followed by silica gel chromatography, formed 3-ethoxycarbonyl-6,7-dihydro-9.10-dimethoxybenzo[a]quinolizin-4-one (6). The same reaction of (3) with (2), followed by reduction with sodium borohydride, afforded 3-ethoxycarbonyl-2-diethoxycarbonylmethyl-1,2,3,6,7,11b-hexahydro-9,10-dimethoxybenzo[a]quinolizin-4-one(10).Condensation of (3) with dimethyl 3-methoxyallylidenemalonate (11) gave 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methoxycarbonyl-2-(ββ-dimethoxyethyl)benzo[a]quinolizin-4-one (13), which was converted to (±)-emetine (1) in seven steps and (±)-dihydroprotoemetine (2) in six steps.Decarboxylation of the enamide form (22) furnished mainly the cis-substituted compound (23).

A carbon–carbon bond formation reaction at the C-4 position of a β-lactam

Upon treatment with various organolithiums, 4-acetoxyazetidin-2-one (10) afforded the corresponding carbondisplaced compounds (11), (12), and (13). 4-(3-Diazo-3-ethoxycarbonyl-2-oxopropyl)azetidin-2-one (15) was also synthesised from (10) and ethyl α-diazoacetoacetate in the presence of lithium hexamethyldisilazide in one step. The diazo-compound (15) was thermally cyclised to the bicyclic keto-ester (17) in the presence of rhodium acetate.

Synthesis and cytotoxic activity of novel 10-alkylated docetaxel analogs.

An alkylation method of docetaxel at the C-10 position has been established by a radical coupling reaction using a 10-xanthate derivative of 7-O-TES-10-deacetylbaccatin III and appropriate alkenes. In addition the cytotoxic activity of 10-alkylated docetaxel analogs was evaluated. Among these analogs, a derivative having a methoxycarbonyl group at the end of the alkyl moiety exhibited more potent cytotoxic activity than docetaxel.

First synthesis and cytotoxic activity of novel docetaxel analogs modified at the C18-position

Abstract To investigate the effect of the C-18 position of docetaxel in its cytotoxic activity, 18-modified docetaxel analogs were synthesized for the first time from the 18-brominated baccatin derivatives. All of these analogs were found to be less active than docetaxel in cytotoxic activity against four test cell lines.