Synthesis and antitumor activity of novel C-7 paclitaxel ethers: discovery of BMS-184476.

The preparation of C-7 paclitaxel ethers is described. Various substituted ethers were prepared via activation of the corresponding methylthiomethyl ether followed by alcohol addition. Variation of the C-7 ether group as well the 3' side chain position led to the discovery of a novel taxane, BMS-184476 (4), with preclinical antitumor activity superior to paclitaxel.

Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative.

PURPOSE: A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally. METHODS: Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose. RESULTS: BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7-2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/ cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route. CONCLUSION: The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development.

Himastatin, a new antitumor antibiotic from Streptomyces hygroscopicus. III. Structural elucidation.

The structure of the antitumor antibiotic himastatin was determined using a combination of spectroscopic and chemical degradation techniques. Himastatin is a unique dimeric cyclohexadepsipeptide joined through a biphenyl linkage between two oxidized tryptophan units. The gross structure of the dimer was established through degradative ozonolysis. Himastatin consists of D-valine, D-threonine, L-leucine, L-alpha-hydroxyisovaleric acid, (3R,5R)-5-hydroxypiperazic acid, and (2R,3aR,8aR)-3a-hydroxyhexahydropyrrolo[2,3b]indole 2-carboxylic acid subunits.

Esperamicin P, the tetrasulfide analog of esperamicin A1.

A minor congener of esperamicin A1 [1], designated esperamicin P (BMY-41339, 2), was isolated from a fermentation broth of Actinomadura verrucosospora and determined to differ from esperamicin A1 by having a methyl tetrasulfide moiety instead of a methyl trisulfide. It was active against xenografted tumors in mice and exhibited antimicrobial activity. Interconversions of 2 and 1 have been observed for DMSO solutions of both congeners at room temperature.

Determination of DNA cleavage specificity by esperamicins.

The esperamicins are members of a class of potent antitumor antibiotics that contain stained diacetylenic ring systems capable of forming DNA-cleaving diradicals upon reaction with thiols. Here we show that the diacetylenic ring core itself determines the sequence specificity for scission of duplex DNA): esperamicin A1, and three products of hydrolysis of the glycon, esperamicins C, D, and E, are found to retain a common sequence preference. The sugar residues exert a strong influence on the cleavage efficiency, presumably by interacting nonspecifically with DNA. The presence of a branch in the DNA is found locally to inhibit scission by esperamicins, and this effect is shown to be due to the core also.

AT2433-A1, AT2433-A2, AT2433-B1 and AT2433-B2 novel antitumor compounds produced by Actinomadura melliaura. II. Structure determination.

The chemical structures of AT2433-A1 (2), AT2433-A2 (3), AT2433-B1 (4) and AT2433-B2 (5) were elucidated by degradation and spectroscopic studies. Compounds 2-5 are disaccharides closely related to rebeccamycin. The aglycone in 2 and 3 was determined to be 6-N-methyl-11-chloro-5H-indolo[2,3-a]pyrolo[3,4-c]carbazole and in 4 and 5 it was determined to be 6-N-methyl-5H-indolo[2,3-a]pyrolo[3,4-c]carbazole. Compounds 2 and 4 are 4-N"-methyl analogs of 3 and 5.

Nucleotide-specific cleavage and minor-groove interaction of DNA with esperamicin antitumor antibiotics.

The cleavage of DNA by esperamicin is greatly accelerated in the presence of thiol compounds. Oxygen and active oxygen-radical scavengers have no significant influence upon DNA strand breakage by esperamicin. The preferential cutting sites of esperamicin are at thymidylate residues, and the frequency of bases attacked (T greater than C greater than A greater than G) is different from that of calicheamicin (C much greater than T greater than A = G), neocarzinostatin (T greater than A greater than C greater than G), or bleomycin (C greater than T greater than A greater than G). Esperamicin preferentially attacks at T and C bases in oligopyrimidine sequences such as 5'-CTC-3', 5'-TTC-3', and 5'-TTT-3'. In contrast to the preferred sites of cleavage by bleomycin, 5'-GT-3' and 5'-GC-3', the preferred sites of esperamicin-mediated DNA degradation are 5'-TG-3' and 5'-CG-3' sequences. The nucleotide-specific cleavage mode of esperamicin is significantly affected by pretreatment of DNA with netropsin and distamycin A, suggesting that interaction of esperamicin occurs through the minor groove of B-DNA. This is further supported by the asymmetric cleavage pattern to the 3' side on the opposite strand of the DNA. The roles of the fucose-anthranilate moiety and the trisaccharide side chain of esperamicin in DNA binding and base recognition are discussed.

Esperamicins, a class of potent antitumor antibiotics: mechanism of action.

The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single- and double-strand DNA breaks. Using five structurally related analogs, we defined a structure-activity relationship for cytotoxicity in various eukaryotic and DNA-repair-deficient prokaryotic cell lines, for DNA breakage in a human colon carcinoma cell line, and for DNA breakage in vitro in pBR322 DNA. Mild reducing agents such as dithiothreitol greatly increased the DNA breakage potency of these analogs in vitro. Results suggest that the pendant aromatic chromophore of esperamicin A1 may contribute to the uptake of the drug into cells but may also hinder double-strand DNA break formation. Little DNA breakage specificity was observed for the drug in a 139-base-pair fragment of pBR322 DNA. Evidence supports a previously proposed mechanism whereby esperamicins may produce the observed DNA breaks through reduction of the methyl trisulfide group to a thiolate anion followed by a Michael addition of the anion across the alpha,beta-unsaturated ketone. This addition may result in the saturation of the bridgehead double bond, thus allowing the two triple bonds to approach each other, causing cyclization of the diyn-ene to form a phenylene diradical. It is likely that this diradical is the active form of the drug responsible for single- and double-strand DNA breakage produced by this class of antitumor agents.

The structure of lienomycin, a pentaene macrolide antitumor antibiotic. I. The structure of the carbon skeleton and the location of functionalities.

The structure of a novel type of pentaene macrolide named lienomycin (I) was established by selected chemical transformations of I followed by MS examination of the products. This report provides evidence on the structure of the carbon skeleton of I and on the location of functionalities.

The structure of lienomycin, a pentaene macrolide antitumor antibiotic. II. The location of the pentaene chromophore and of six isolated double bonds. The complete structure of the antibiotic.

The locations of the isolated double bonds and of the pentaene chromophore in lienomycin (I) were established by chemical degradation of I followed by MS and 1H NMR examination of the products. The complete structure of the antibiotic is proposed.