Jamshed H. Shah

Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198

Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G2-M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1α levels. ENMD-1198 and ENMD-1200 showed improved in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung carcinoma metastatic model (P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide. ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients with refractory solid tumors. [Mol Cancer Ther 2008;7(6):1472–82]

Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs

The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol.

Synthesis of 2- and 17-substituted estrone analogs and their antiproliferative structure–activity relationships compared to 2-methoxyestradiol

A novel series of 17-modified and 2,17-modified analogs of 2-methoxyestradiol (2ME2) were synthesized and characterized. These analogs were designed to retain or potentiate the biological activities of 2ME2 and have diminished metabolic liability. The analogs were evaluated for antiproliferative activity against MDA-MB-231 breast tumor cells, antiangiogenic activity in HUVEC, and estrogenic activity on MCF-7 cell proliferation. Several analogs were evaluated for metabolic stability in human liver microsomes and in vivo in a rat cassette dosing model. This study lead to several 17-modified analogs of 2ME2 that have similar or improved antiproliferative and antiangiogenic activity, lack estrogenic properties and have improved metabolic stability compared to 2ME2.

Synthesis, antiproliferative, and pharmacokinetic properties of 3- and 17-double-modified analogs of 2-methoxyestradiol.

The syntheses of 21 analogs of 2-methoxyestradiol are presented, including ENMD-1198 which was selected for advancement into Phase 1 clinical trials in oncology. These analogs were evaluated for antiproliferative activity using breast tumor MDA-MB-231 cells, for antiangiogenic activity in HUVEC proliferation assays, and for estrogenic activity in MCF-7 cell proliferation. The most active analogs were evaluated for iv and oral pharmacokinetic properties via cassette dosing in rat and in mice pharmacokinetic models.

Effect of Absolute Configuration on the Optical and NMR Properties of Oligonucleotides Containing Benzo[a]Pyrene Adducts at N 6 of Deoxyadenosine

Abstract For oligonucleotide duplexes derived from trans opening of benzo[a]pyrene diol epoxides (BaP DEs) by the exocyclic N6-amino group of deoxyadenosine (dA), the hydrocarbon is intercalated toward the 5′-end of the modified strand when the configuration at the site of attachment of the base to the hydrocarbon (C-10) is R, and toward the 3′-end when this configuration is S. In oligonucleotide 11-mer duplexes modified by BaP DE-1 (benzylic 7-OH and epoxide oxygen cis) and DE-2 (7-OH and epoxide oxygen trans), as well as 7,8,9,10-tetrahydro BaP 9,10-epoxide, 10R adducts had consistently higher (5–9d°C) Tm values than the corresponding 10S adducts. Dodecamer duplexes from the HPRT gene with trans opened 10S (but not those with 10R) BaP DE-2 adducts at either of two adjacent dA residues exhibited blue shifts at ∼350 nm at temperatures well below the Tm. We propose that these blue shifts result from a conformation in which the hydrocarbon is not stacked with the DNA bases.