nsc-600032 and Leukemia-P388

Efficient syntheses of 3,4-methylenedioxy-4',5-dimethoxy-2',3'-dihydroxy-Z-stilbene (stilstatin 1, 2), 3,4,4'-trimethoxy-2',3',5-trihydroxy-Z-stilbene (stilstatin 2, 5), and respective phosphate prodrugs have been summarized. Both 2 and 5 were accessed via a convergent step synthesis using phosphonium bromides 6 and 21 in Wittig reactions with 2,3-bis(tert-butyldimethylsilyloxy)-4'-methoxybenzaldehyde 14. Deprotection of silyl ethers 15 and 26 with TBAF furnished 2 and 5, respectively. Phosphorylation of 2 and 5 afforded the phosphoric acid intermediates 17 and 28 for prodrug development. These phosphoric acid precursors were employed in parallel series of reactions to produce a selection of metal cation prodrug candidates. The biological activities of stilstatins 1 (2) and 2 (5) and their respective prodrugs were evaluated against a panel of one murine (P388) and six human cancer cell lines. Compared to combretastatin A-2 (1), stilstatin 1 (2) has an additional vicinal hydroxy group on the B ring, the presence of which was detrimental to the cancer cell line potency; in vivo, however, compound 2 would be predicted to have greater anticancer activity resulting from the o-quinone mechanism of action analogous to that of combretastatin A-1 (4). The substitution of a hydroxy group for a methoxy group on the A ring of combretastatin A-1 (4), resulting in stilstatin 2 (5), gave rise to a modest level of inhibition consistent with that found for 4 against cancer cell lines.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Female; Humans; Leukemia P388; Male; Mice; Molecular Structure; Prodrugs; Solubility; Stereoisomerism; Stilbenes; Water

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia P388; Mice; Molecular Structure; Neoplasms; Regional Blood Flow; Stilbenes; Tubulin

The very unstable (<10 min at rt) o-quinone 5 derived from the vicinal diphenol anticancer drug combretastatin A-1 (1) has been obtained by careful oxidation with NaIO4 and tetrabutylammonium bromide in water/dichloromethane. Immediate reaction with phenylenediamine (6) allowed o-quinone 5 to be trapped as the stable phenazine derivative 7. For further confirmation, 5 was also captured as a dimethoxyphenylenediamine-derived phenazine (11). Both phenazines 7 and 11 significantly inhibited (ED50 approximately 0.2 microg/mL) growth of the murine P388 lymphocytic leukemia cell line and provided a new SAR insight in the combretastatin series of naturally occurring anticancer drugs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Products; Drug Screening Assays, Antitumor; Leukemia P388; Molecular Structure; Oxidation-Reduction; Prodrugs; Quinones; Stilbenes; Structure-Activity Relationship

The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (>10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 --> 8a --> 11a --> 14 --> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (1a) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Cryptococcus neoformans; Drug Screening Assays, Antitumor; Humans; Hydrocarbons, Halogenated; Leukemia P388; Molecular Structure; Stereoisomerism; Stilbenes; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured

Combretastatin A4, a novel anti-mitotic agent was effective against two P388 cell lines with acquired resistance to daunorubicin. In contrast, Combretastatin A1, a close structural analogue of A4, showed a high degree of cross-resistance. Combretastatin A1 was also more efficient at increasing intracellular daunorubicin concentrations in both resistant cell lines. Neither agent was capable of altering anthracycline accumulation in the parental (sensitive) cell line. We propose that the cross-resistance to Combretastatin A1 occurs, at least in part, as a result of the increased affinity of the drug-efflux process operative in these resistant cells for Combretastatin A1 vs Combretastatin A4. Hence, Combretastatin A4 may play a role in the treatment of tumours with acquired resistance to the anthracycline antibiotics.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Survival; Daunorubicin; Drug Interactions; Drug Resistance; Leukemia P388; Mice; Stilbenes; Tumor Cells, Cultured; Vinca Alkaloids