ABSTRACT
Natural product seselin and related derivatives with an angular pyranocoumarin skeleton were synthesized from 8-acetyl-7-hydroxycoumarins by condensation with acetone, reduction, and dehydration successively under mild conditions with total yield of > 50%. Twelve seselin derivatives were tested by the writhing response assay induced by acetic acid at a dose of 40 mg x kg(-1). Seselin (4a) and 4,8,8-trimethyl-9,9-dihydro-pyran[2,3-f] chromene-2,10-dione (2b) showed obviously antinociceptive activity with inhibitory effect of 85% and 50%, respectively, more or quite potent than aspirin in the same assay, suggesting that seselin derivatives could be a novel kind of potential antinociceptive agents.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Chromones/chemical synthesis , Chromones/pharmacology , Coumarins/chemical synthesis , Coumarins/pharmacology , Analgesics/chemistry , Animals , Chromones/chemistry , Coumarins/chemistry , Female , Male , Mice , Molecular Structure , Pain Measurement/drug effectsABSTRACT
In prior investigation, we discovered that (3'R,4'R)-3-cyanomethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (4, 3-cyanomethyl-4-methyl-DCK) showed promising anti-HIV activity. In these current studies, we developed and optimized successfully a practical 10-step synthesis for scale-up preparation to increase the overall yield of 4 from 7.8% to 32%. Furthermore, compound 4 exhibited broad-spectrum anti-HIV activity against wild-type and drug-resistant viral infection of CD4+ T cell lines as well as peripheral blood mononuclear cells by both laboratory-adapted and primary HIV-1 isolates with distinct subtypes and tropisms. Compound 4 was further subjected to in vitro and in vivo pharmacokinetic studies. These studies indicated that 4 has moderate cell permeability, moderate oral bioavailability, and low systemic clearance. These results suggest that 4 should be developed as a promising anti-HIV agent for development as a clinical trial candidate.
Subject(s)
Anti-HIV Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , CD4-Positive T-Lymphocytes/drug effects , Chemistry, Pharmaceutical/methods , Coumarins/chemical synthesis , Coumarins/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/pharmacology , Area Under Curve , Bridged Bicyclo Compounds, Heterocyclic/chemistry , CD4-Positive T-Lymphocytes/metabolism , Coumarins/chemistry , Drug Design , Drug Evaluation, Preclinical , HIV-1/metabolism , Humans , Male , Models, Chemical , Rats , Rats, Sprague-DawleyABSTRACT
Twenty-six unsymmetrical biphenyls were synthesized and evaluated for cytotoxic activity against DU145, A549, KB and KB-Vin tumor cell lines. Three compounds 27, 35 and 40 showed very potent activity against the HTCL panel with an IC(50) value range of 0.04-3.23 microM. In addition, fourteen active compounds were all more potent against the drug-resistant KB-Vin cell line than the parental KB cell line. Preliminary SAR analysis indicated that two bulky substituents on the 2,2'-positions of unsymmetrical biphenyl skeleton are necessary and crucial for in vitro anticancer activity, thus providing a good starting point to develop unsymmetrical biphenyls as novel anticancer agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Antineoplastic Agents/chemistry , Biphenyl Compounds/chemistry , Cell Line, Tumor , Combinatorial Chemistry Techniques , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , MaleABSTRACT
3',4'-Di-O-(S)-comphanoyl-(+)-cis-khellactone (DCK) is a synthetic khellactone ester that exhibits potent anti-HIV activity with a mechanism distinct from clinically used anti-HIV agents. Several series of DCK analoges have been synthesized and evaluated for inhibitory effects against HIV. This review article describes recent progress in the discovery, structural modification, and structure-activity relationship studies of potent anti-HIV DCK derivatives.
