ABSTRACT
EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine), a nucleoside reverse transcriptase inhibitor with extremely potent anti-HIV activity, was concisely synthesized from (R)-glyceraldehyde acetonide in an 18% overall yield by a 12-step sequence involving highly diastereoselective ethynylation of an α-alkoxy ketone intermediate. The present synthesis is superior, both in overall yield and in the number of steps, to the previous one which required 18 steps from an expensive starting material and resulted in a modest overall yield of 2.5%.
Subject(s)
Anti-HIV Agents/chemical synthesis , Deoxyadenosines/chemical synthesis , Glyceraldehyde/analogs & derivatives , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/chemical synthesis , Glyceraldehyde/chemistry , HIV/enzymology , HIV Reverse Transcriptase/chemistry , Humans , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Haplorhini , Humans , Lung Neoplasms/drug therapy , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbazoles/chemical synthesis , Piperazines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , In Vitro Techniques , Macaca fascicularis , Male , Mice , Mice, SCID , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A concise synthesis of di-O-methyl-beta,gamma-dehydrocurvularin, the di-O-methylated derivative of the naturally occurring nematicidal macrolide, beta,gamma-dehydrocurvuralin, was accomplished by starting from a commercially available aromatic carboxylic acid in a three-step sequence consisting of esterification, Friedel-Crafts acylation, and microwave-promoted ring-closing metathesis.
