Synthesis and antifungal activities of novel 1,3-beta-D-glucan synthase inhibitors. Part 2.

Highly potent 1,3-beta-D-glucan synthase inhibitors, 7b, 10a, 10b and 12, have been identified by the chemical modification of the ornithine residue of a fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. These compounds showed stronger antifungal activity against systemic candidiasis as well as pulmonary aspergillosis in mice, and less hepatotoxicity as compared with 1.

The dithiane Ro 44-5912 enhances vinblastine sensitivity of drug resistant and parental KB lines in vivo.

The multidrug resistance modifying activity of a dithiane analogue of tiapamil, Ro 44-5912, was examined in vivo. Results of acute toxicity studies in mice indicated that lethal toxicity occurred with doses greater than 1 mmol/kg of body weight. In a preliminary pharmacokinetic investigation, Ro 44-5912 appeared to have a longer half-life in mice than did its (R) enantiomer Ro 44-5911 (3.15 +/- 0.02 h versus 2.15 +/- 0.14 h) as measured by total radiolabel in plasma. In non-tumour bearing mice, Ro 44-5912 enhanced the toxicity of vinblastine in a manner that was dependent on the dose of both drugs. Vinblastine did not have a significant effect on tumour growth when given to nude mice bearing the parental cell line KB-3-1 at a dose of 1.5 mg/kg once per week for 3 weeks. Combination treatment with Ro 44-5912 markedly enhanced the antitumour activity of vinblastine. Similar results were seen when KB-3-1 tumours were treated with the combination of vinblastine plus cyclosporin A. Another tiapamil analogue, Ro 11-2933, had no enhancing activity with this tumour when used at an equitoxic combination dose. Ro 44-5912 also significantly enhanced vinblastine activity with P-glycoprotein-expressing KB-8-5 tumours. In three independent experiments, Ro 44-5912 enhanced the growth inhibiting activity of vinblastine by a mean of approximately 40%. Neither Ro-11-2933 nor cyclosporin A, at the maximal tolerated doses in combination with vinblastine, led to significant inhibition of KB-8-5 tumour growth compared to treatment with the two vehicles alone. These results show that Ro 44-5912 is an active modulator of drug resistance in vivo.

Anti-proliferative effects of the arotinoid Ro 40-8757 on human cancer cell lines in vitro.

A novel arotinoid with a morpholine structure in the polar end group Ro 40-8757 (4-[2-[p-[(E)-2(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy]ethyl]-morpholine) was tested for its anti-proliferative activity against nine human cancer cell lines in vitro. The lines included two estrogen receptor positive breast cancer lines (MCF-7 and ZR-75-1), two estrogen receptor negative breast cancer lines (MDA-MB-231 and BT-20), one cervix carcinoma line (KB-3-1), two lung adenocarcinoma lines (A549 and HLC-1), one large cell lung cancer line (LXFL 529) and two colorectal lines (CXF 243 and CXF 280). Proliferation of all the lines, except the two lung adenocarcinoma lines, was inhibited by lower concentrations of Ro 40-8757 than those of all-trans retinoic acid (RA) or 13-cis RA giving the same level of inhibition. The degree of inhibition of RO 40-8757 was concentration and time dependent. The arotinoid was not cytotoxic and morphological signs by differentiation were not evident in cultures treated with Ro 40-8757 for up to 2 weeks. Because this compound is active on cells such as KB-3-1 that are not inhibited by all-trans RA and because it does not bind to nuclear retinoic acid receptors, it may represent a novel class of anti-proliferative agents.

Comparison of the therapeutic effects of a new arotinoid, Ro 40-8757, and all-trans- and 13-cis-retinoic acids on rat breast cancer.

A novel arotinoid, 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl)propenyl]phenoxy))ethyl))-morpholine, was tested in rats bearing established chemically induced mammary tumors. At a dose of 0.35 mmol/kg/day of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine, decreased tumor growth was seen after 2 weeks. By weeks 4 and 5, tumor burdens were decreased to 10-30% of initial values and 50-70% of the animals became free of palpable tumors. Stabilization of tumor size through 15 weeks of treatment was seen in rats given 0.23 mmol/kg/day of the arotinoid. The predominate adverse effects of this compound were dose-dependent weight loss during the first 1-3 weeks, attributed to poor palatability of the food admix as well as flaking of the skin and alopecia at later times. Bone toxicity, a characteristic side effect of retinoids in rodents, was rare with this arotinoid, mainly confined to young rats treated for more than 12 weeks with high doses. In a comparative study, neither all-trans-retinoic acid nor 13-cis-retinoic acid had significant antitumor effects at doses that were tolerated by the animals. When all-trans-retinoic acid was administered at 0.08 mmol/kg/day, tumor reduction was seen during weeks 4-6, but treatment was terminated after week 6 due to severe skeletal toxicity and general deterioration in all the animals. Such marked toxicity was not evident with the arotinoid at doses having high antitumor activity. The high efficacy and relatively low toxicity of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine suggest that it may be a promising new anticancer agent.