ABSTRACT
The potential therapeutic application of the naturally occurring, cytotoxic pseudoguaianolide sesquiterpene lactone ambrosin is limited by its aqueous insolubility. A number of water-soluble ambrosin derivatives have therefore been prepared for potential use as prodrugs. Michael addition of several secondary amines to both the alpha,beta-unsaturated ketone and alpha-methylene lactone moieties of ambrosin afforded tertiary amine diadducts that were converted to water-soluble hydrochloride salts. The salt of the bis-piperidine adduct proved to be the most potent, producing cytotoxic activity only slightly less potent than that of ambrosin itself in a variety of human cancer cell cultures. The sodium salt of the bis-sulfonic acid derivative of ambrosin was inactive, while the sodium salt of the bis-sulfinic acid analog had low activity. Biological evaluation of several ambrosin analogs with reduced and/or isomerized alpha,beta-unsaturated ketone and alpha-methylene lactone moieties demonstrated the importance of both of these functional groups for biological activity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Prodrugs/chemical synthesis , Sesquiterpenes/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Prodrugs/chemistry , Prodrugs/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Sesquiterpenes, Guaiane , Tumor Cells, CulturedABSTRACT
Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3"-dichloro-4',4"-dimethoxy-5', 5"-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 microM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.
Subject(s)
Alkanes , Anti-HIV Agents , Caproates , HIV-1/drug effects , Reverse Transcriptase Inhibitors , Alkanes/chemical synthesis , Alkanes/chemistry , Alkanes/metabolism , Alkanes/pharmacology , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Binding Sites , Caproates/chemical synthesis , Caproates/chemistry , Caproates/metabolism , Caproates/pharmacology , Cell Line , Cytopathogenic Effect, Viral/drug effects , Drug Evaluation, Preclinical , Drug Resistance, Microbial , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HIV-1/genetics , HIV-1/physiology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Macrophages/drug effects , Macrophages/virology , Mice , Models, Molecular , Mutation , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/virology , Virus Replication/drug effects , Zidovudine/pharmacologyABSTRACT
The preparation of a number of new N-substituted derivatives of 7-diphenylmethylenebicyclo[2.2.1]hept-2-ene-5,6-dicarboximide with an expected anxiolytic activity.