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.

Synthesis and evaluation of water-soluble non-prodrug analogs of docetaxel bearing sec-aminoethyl group at the C-10 position.

To develop non-prodrugs of taxoids with satisfactory stability in vivo, high water-solubility, and potent antitumor activity, we prepared several 10-O-sec-aminoethyl docetaxel analogs (3) and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines, microtubule disassembly-inhibitory activity, and water-solubility. These analogs were synthesized from the 10-O-allyl baccatin derivatives (5a-c) using the beta-lactam synthon method. Among these analogs, the 10-O-(2-morpholinoethyl) (18, 21) and 10-O-(2-thiomorpholinoethyl) (19, 24) analogs exhibited cytotoxicity comparable or superior to that of docetaxel (2). In addition, the methanesulfonic acid salt (18a) had a high water-solubility.

Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.

Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.

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.

Synthesis and structure-activity relationships of novel 2',2'-difluoro analogues of docetaxel.

To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2',2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1 and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p) analogues showed activity comparable or superior to that of docetaxel (2).

A new method to modify the C-4 position of 10-deacetylbaccatin III.

We have developed a new method to modify the C-4 position of 10-deacetylbaccatin III (5) using the C-4 acetoxy anion of the 13-keto derivative (7) and various alkyl halides. The method developed herein should be very useful for the preparation of C-4 modified taxoid analogs.

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.

Antitumor agents. 7. Synthesis and antitumor activity of novel hexacyclic camptothecin analogues.

Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.

Zinc triflate-promoted glycosidation: synthesis of lipid A disaccharide intermediates.

Zinc triflate was found to be superior to the heavy metal salts as a promoter in the Koenigs-Knorr type glycosidation reaction in the synthesis of lipid A disaccharide intermediates. It readily promoted the reaction of a complex glycosyl bromide with a reducing sugar moiety and gave the disaccharide with beta-selectivity in good yield. This method would be suitable for the bulk preparation of lipid A disaccharide intermediates.

Synthesis and biological activities of lipid A analogs: modification of a glycosidically bound group with chemically stable polar acidic groups and lipophilic groups on the disaccharide backbone with tetradecanoyl or N-dodecanoylglycyl groups.

Six novel lipid A analogs were synthesized. The first two analogs, 4 and 5, have an alpha-glycosidically bound carboxymethyl or 1,3-dicarboxyisopropyl group on the disaccharide backbone with four tetradecanoyl groups. The next three analogs, 6, 7 and 8, have two or four N-dodecanoylglycyl groups on the 1-alpha-O-phosphonooxyethylated disaccharide backbone. Analog 6 bears N-dodecanoylglycyl groups on the hydroxyl functions at positions 3 and 3', and tetradecanoyl groups on the amino functions at positions 2 and 2'. Analog 7 is a 2, 3, 2' and 3'-tetrakis(N-dodecanoylglycyl) derivative, and analog 8 resembles compound 6, but the binding of the N-dodecanoylglycyl and tetradecanoyl groups at positions 2, 2' and 3, 3' are reversed. The third analog, 9, has the same acyl group configuration as compound 6, but has a 1,3-dicarboxyisopropyl group at position C-1. Compounds 4 and 5 exhibited definite antitumor activity against Meth A fibrosarcoma, indicating that the phosphate group at the C-1 position in lipid A could be replaced by the carboxylic acid without reducing the antitumor activity. In rabbits, compounds 6 and 9 exhibited potent antitumor activity, but their toxicity was extremely low. On the other hand, compounds 7 and 8 showed no antitumor activity. The levels of antitumor activity of 6 and 9 were similar to those of the natural-type lipid A. The antitumor activities of analogs with a N-dodecanoylglycyl group on the disaccharide backbone depended on the connecting sites of the acyl groups.