Robert C. Kelly

Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065

SummaryAdozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p.- or s.c.-implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.

Taxol chemistry. 7-O-triflates as precursors to olefins and cyclopropanes

Abstract 7-O-Triflates of baccatin III or of taxol analogs are convenient precursors in alternate syntheses of Δ 6,7 -taxols and 7β,8β-methano (cyclopropyl) taxols, two of the products initially obtained from reaction of taxols with methylDAST; hydrazine is an effective reagent for conversion of the 10-acetate group to the hydroxyl group.

Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives

Abstract Although cytarabine (cytosine arabinoside, ara -cytidine, Cytosar) is a potent immunosuppressant, antiviral and antitumor agent in animals and man, maximum inhibitory effects require the use of complex injection schedules. Previous reports have shown that good immunosuppressive and antitumor activities were attained with simple injection schedules using the 5′-adamantoate derivative. The current results show that a variety of 5′-acylates were equally as active as the 5′-adamantoate in suppressing immune responses in rodents (hemagglutinin formation in mice and hamsters, skin graft rejection in rats), and as antitumor agents in mice (L1210 leukemia). Similar results were attained in protecting mice from the lethal effects of intracranial herpes simplex infection, and in inhibiting DNA synthesis in phytohemagglutinin-stimulated human lymphocytes. The hypothesis for the enhanced potency of these newer derivatives was as follows: After injection of these insoluble derivatives, there is a finite time required for dispersion and solubilization. The freely circulating derivatives are resistant to deamination (and inactivation). After enzymatic hydrolysis to the free acid and cytarabine, the latter is then free to exert its inhibitory activities. The net effect is the maintenance of relatively low levels of cytarabine for long periods of time.

Structure and activity relationship of several novel CC-1065 analogs

SummaryCC-1065 was found to cause delayed toxicity at therapeutic doses, therefore, a large number of analogs have since been synthesized. A series of analogs with simplified but closely related structures were chosen for this investigation because some were found to be superior to CC-1065 in the treatment of several experimental tumors. The inhibition of L1210 cell growth by U-68,415 was comparable to that by CC-1065. A similar situation was true in terms of their in vivo potency; however, U-68,415 was superior to CC-1065 in terms of anti-P 388 leukemia activity. At the optimal dosage, U-68,415 produced 4 out of 6 long-term (> 30 day) survivors; whereas CC-1065 produced a mere 62% increase of life span (ILS) and no long-term survivors. The order of antitumor potency and effectiveness of the CC-1065 analogs was U-68,415 > U-66,694 > U-68,819 > U-66,664, which was parallel to the inhibition of L1210 cell growth. CC-1065 and all the analogs tested here inhibited DNA synthesis approximately 10 times more than RNA synthesis. Protein synthesis was the least inhibited. On a molar basis, U-68,415 was about 6–9 times more inhibitory toward cellular DNA synthesis than CC-1065, yet the interaction and/or binding of CC-1065 to DNA determined by circular dichroism, DNA melting or differential cytotoxicity assay was much stronger than that of U-68,415. The order of binding of these analogs to calf thymus DNA was U-68,415 > U-66,694 > U-68,819 > U-66,664, and was parallel to that of DNA synthesis inhibition which was in turn parallel to cell growth inhibition and antitumor potential. These results collectively suggest that the cellular DNA is a major site of the action of CC-1065 analogs; however, time course studies reveal that the inhibition of cellular DNA synthesis could not wholly account for their cytotoxicity. Hence, the precise mechanism of action of these agents is not yet fully understood. U-68,415, which exhibited superior activity against a number of tumors and did not cause delayed death in mice, warrants further investigation. U-68,415 is a racemate and two chiral isomers were recently isolated. Therefore, further investigation of both U-68,415 and its chiral isomers is necessary.

A Direct Alcohol for Hydrazine Interchange: Scope and Stereochemistry

Abstract In 1967 an interesting esterification of carboxylic and phosphoric acids with alcohols in the presence of triphenyl-phosphine and diethylazodicarboxylate was reported by Mitsunobu, Yamada, and Mukaiyama.1,2 One intriguing aspect of this “Mitsunobu” reaction (Reaction 1) was that it proceeded with inversion of configuration of the alcohol.2,3 A second remarkable facet of this dehydrative redox coupling reaction was the general adaptability to a wide variety of substitution reactions on alcohols. Examples of such intermolecular substitutions include

Stereoselective synthesis of a synthon for the A-ring of taxol from R-(+)-verbenone

Abstract The efficient conversion of R-(+)-verbenone to bicyclic lactone 6 , a potentially useful intermediate for the synthesis of taxanes, is described. The introduction of C-1 (taxane numbering) oxygen functionality is also reported, thereby completing the synthesis of the A-ring subunit of taxol.

SYNTHESIS OF THROMBOXANES

The recognition that thromboxanes represent an important branch in the arachidonic acid-prostag landin pathway has prompted efforts on our part to synthesize thromboxane B 2 as an initial goal. This report describes two total syntheses and one partial synthesis of this substance.