ABSTRACT
Three novel steroidal antiestrogen-geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11ß-(4-functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity.
Subject(s)
Benzoquinones/chemical synthesis , Benzoquinones/pharmacology , Breast Neoplasms/drug therapy , Estrogen Antagonists/chemical synthesis , Estrogen Antagonists/pharmacology , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/pharmacology , Benzoquinones/chemistry , Breast Neoplasms/metabolism , Click Chemistry , Drug Screening Assays, Antitumor , Estrogen Antagonists/chemistry , Female , Humans , Lactams, Macrocyclic/chemistry , MCF-7 Cells , Molecular StructureABSTRACT
The synthesis and optimization of a series of orally bioavailable 1-(1H-indol-4-yl)-3,5-disubstituted benzene analogues as antimitotic agents are described. A functionalized dibromobenzene intermediate was used as a key scaffold, which when modified by sequential Suzuki coupling and Buchwald-Hartwig amination provided a flexible entry to 1,3,5-trisubstituted phenyl compounds. A 1H-indol-4-yl moiety at the 1-position was determined to be a critical feature for optimal potency. The compounds have been shown to induce cell cycle arrest at the G2/M phase and demonstrate efficacy in both cell viability and cell proliferation assays. The primary site of action for these agents is revealed by their colchicine competitive inhibition of tubulin polymerization, and a computational model has been developed for the association of these compounds to tubulin. An optimized lead LP-261 significantly inhibits growth of a human non-small-cell lung tumor (NCI-H522) in a mouse xenograft model.
Subject(s)
Indoles/chemical synthesis , Isonicotinic Acids/chemical synthesis , Sulfonamides/chemical synthesis , Tubulin Modulators/chemical synthesis , Animals , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colchicine/chemistry , Drug Screening Assays, Antitumor , G2 Phase , Humans , Indoles/chemistry , Indoles/pharmacology , Isonicotinic Acids/chemistry , Isonicotinic Acids/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transplantation, Heterologous , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new bond between two nucleophiles. In the synthesis, the absolute stereochemistry of the final natural product is set relative to a methyl group that is incorporated early in the sequence using an asymmetric Michael reaction.
Subject(s)
Sesquiterpenes/chemical synthesis , Agaricales/chemistry , StereoisomerismABSTRACT
An anodic cyclization-Friedel Crafts alkylation strategy has been used to rapidly assemble the core ring system of alliacol A and to complete a formal total synthesis of the natural product. The anodic cyclization reaction was used to effect the coupling of a nucleophilic furan ring to the normally nucleophilic carbon of a silyl enol ether. The substrate for this initial cyclization reaction contained all of the carbons needed for completing the total synthesis. The electrolysis proceeded in high yield and could be accomplished with the use of a 6 V lantern battery.
