HIV-1 neutralization and tumor cell proliferation inhibition in vitro by simplified analogues of pyrido[4,3,2-mn]thiazolo[5,4-b]acridine marine alkaloids.

The antiviral/antitumor marine alkaloid dercitin was used as a lead compound to design analogues with anti-HIV and tumor inhibitory activities. Deletion of structural features contributing to cytotoxicity led to analogues with lowered T-lymphocyte toxicity profiles. One compound, 5, induced complete protection against HIV-1 infectivity in vitro at 12.

A sensitive enzyme-linked immunosorbent assay (ELISA) for testosterone: use of a novel heterologous hapten conjugated to penicillinase.

A microplate enzyme-linked immunosorbent assay (ELISA) has been developed for the measurement of testosterone in plasma. The assay uses a heterologous system consisting of a novel hapten 4-(17 beta-hydroxy-3-oxoestra-4,9-dien-11 beta-yl)butanoic acid (1) conjugated to penicillinase (beta-lactamase). The key reaction in the synthesis of the hapten was the cuprate-mediated 1,4-conjugate addition on 3,3,17,17-bis-ethylenedioxy-5 alpha,10 alpha-oxido-estr-9(11)-ene by the Grignard reagent derived from trimethyl 4-bromoorthobutyrate; this regiospecifically introduces the 11 beta-butanoate function.

New potent topical anti-inflammatory steroids with reduced side effects: derivatives of steroid-16-carboxy esters.

Therapeutic use of anti-inflammatory steroids is limited due to their potential suppressive effects on pituitary-adrenal function and the immune system. Based on the antedrug concept, a new class of potent locally active compounds with reduced risk of side effects has been synthesized from prednisolone by introducing a metabolically labile methoxycarbonyl substituent at C-16. Results of topical application of the lead compound, methyl 11 beta,17 alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (P16CM;1), showed that it was 14 times more potent than prednisolone and that it had a greatly reduced tendency to cause systemic side effects.

Synthesis and structure-activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids.

Eighteen test compounds, in three chemical series, were prepared as potential anti-inflammatory agents and evaluated by the rat hindpaw carrageenan-induced edema assay. The compounds, isosteric with known anti-inflammatory and antiallergic cyclo-oxygenase and lipoxygenase inhibitors, are 10-methyl-9,10-dihydro-9-oxo-2-acridinealkanoic acids, 9,10-dihydro-9-oxo-2-acridinealkanoic acids, and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. Compounds within each of these series differ in the structure of the alkanoic acid side chain.

Pharmacokinetics of prednisolone and its local anti-inflammatory steroid-21-oate ester derivatives. In vitro and in vivo comparative study.

A new class of local anti-inflammatory steroid-21-oate esters synthesized by modifying the ketol side chain of prednisolone was found to exhibit minimal systemic side effects such as pituitary-adrenal suppression. It has been hypothesized that the absence of the systemic toxicities of these steroids is due to the rapid hydrolysis of the carboxylate ester group to inactive and readily excretable acid metabolites. The pharmacokinetics of prednisolone and its two ester derivatives, methyl 20 alpha- and 20 beta-dihydroprednisolonate (P4 alpha and P4 beta), were studied in rats following im administration of doses ranging from 0.