Reference

Synthesis of alkoxy-substituted diaryl compounds and correlation of ring separation with inhibition of tubulin polymerization: differential enhancement of inhibitory effects under suboptimal polymerization reaction conditions

Synthesis of alkoxy-substituted diaryl compounds and correlation of ring separation with inhibition of tubulin polymerization: differential enhancement of inhibitory effects under suboptimal polymerization reaction conditions. Getahun, Zelleka; Jurd, Leonard; Chu, Ping S.; Lin, Chii M.; Hamel, Ernest (Lab. Mol. Pharmacol., Natl. Cancer Inst., Bethesda, MD 20892, USA). J. Med. Chem., 35(6), 1058-67 (English) 1992. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 25 A no. of cytostatic compds. which can be described as diaryl, inhibit tubulin polymn., cause cells to accumulate in mitotic arrest, and competitively inhibit the binding of colchicine to tubulin. They differ, however, in the sepn. of the 2 aryl moieties. To attempt to understand this variability a series of analogs modeled on a benzodioxole series and on a combretastatin series which differed only in the no. of methylene units (ranging from 0-4) sepg.In this article, certain chemicals are used. Some of their cas registry numbers are 71712-07-7 and 117048-59-6 the aryl moieties were prepd. These compds. were evaluated for their effects on tubulin polymn., colchicine binding, and the growth of L1210 murine leukemia cells. In terms of inhibitory effects on tubulin polymn., for the combretastatin series there was an optimal sepn. of the 2 Ph rings by a 2-carbon bridge (I), with progressively decreasing inhibitory activity when the sepn. was by 1 carbon (II), 3 carbons (III), or 4 carbons (IV) (the biphenyl analog V was inactive). The benzodioxole series, however, did not permit the generalizatiin of this finding, because the least active agents prepd. had a 2-carbon bridge, while those with 1 and 3-carbon bridges were nearly equiv. in potency. Submicromolar IC50 values for inhibition of L1210 cell growth were only obtained for II (IC50, 0.2 mM), I (0.07 mM), and III (0.4 mM). While evaluating the effects of these agents on tubulin polymn., with the combretastatin series and with several std. agents apparent potency (in terms of IC50 values) was always lower if the reaction was performed at 30°, with 0.25 mM MgCl2, than at 37°, with 1.0 mM MgCl2. This enhancement of IC50 values in the former system as compared with the latter was particularly dramatic for the less active agents (e.g., IV) as compared with the more active (e.g., I). .

Compositions and methods of administering tubulin-binding agents for the treatment of ocular diseases

Compositions and methods of administering tubulin-binding agents for the treatment of ocular diseases. Sherris, David; Wood, Mark (Oxigene, Inc., USA). PCT Int. Appl. WO 2003006002 A1 23 Jan 2003, 59 pp.Several reagents with their cas registry numbers 7647-14-5 and 117048-59-6 are used here. DESIGNATED STATES: W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM; RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, CY, DE, DK, ES, FI, FR, GA, GB, GR, IE, IT, LU, MC, ML, MR, NE, NL, PT, SE, SN, TD, TG, TR. (English). (World Intellectual Property Organization). CODEN: PIXXD2. CLASS: IC: A61K031-135. APPLICATION: WO 2002-US22449 15 Jul 2002. PRIORITY: US 2002-PV377556 2 May 2002; US 2002-PV377845 3 May 2002. DOCUMENT TYPE: Patent CA Section: 63 (Pharmaceuticals) Section cross-reference(s): 1 The present invention is directed to the administration of vascular targeting agents, particularly a tubulin-binding agent, for the treatment of ocular neovascularization, ocular tumors, and conditions such as diabetic retinopathy, retinopathy of prematurity, retinoblastoma and macular degeneration. .