11a-N-tosyl-5-carbapterocarpans: Synthesis, antineoplastic evaluation and in silico prediction of ADMETox properties.

Abstract

11a-N-tosyl-5-carbapterocarpans (5a-c and 6a-c), 9-N-tosyl-4,4a,9,9a-tetrahydro-3H-carbazole (7), 11a-N-tosyl-5-carbapterocarpen (8) analogues of LQB-223 (4a), were synthesized through palladium catalyzed azaarylation of substituted dihydronaphtalenes (14a-c) and cyclohexadiene (15), respectively, with N-tosyl-o-iodoaniline (11). In order to understand the role of the N-tosyl moiety for the pharmacological activity, the azacarbapterocarpen (9) was also synthesized by Fischer indol reaction. The structural requirements at the A and D-rings for the antineoplastic activity toward human leukemias and breast cancer cells were evaluated as well. Substitutions on the A-ring of 4a and analogues alter the effect on different breast cancer subtypes. On the other hand, A-ring is not essential for antileukemic activity since compound 7, which does not contain the A-ring, showed efficacy with high selectivity indices for drug-resistant leukemias. On the other hand, substitutions on the D-ring of 4a for fluorine or iodine did not improve the antileukemic activity. In silico studies concerning Lipinskís rule of five, ADMET properties and drug scores of those compounds were performed, indicating good physicochemical properties for all compounds, in special for compound 7.

• Authors: Joseane A Mendes, Eduardo J Salustiano, Carulini de S Pires, Thaís Oliveira, Julio C F Barcellos, Jhonny M C Cifuentes, Paulo R R Costa, Magdalena N Rennó, Camilla D Buarque
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 80 Pg. 585-590 (10 2018) ISSN: 1090-2120 [Electronic] United States
• PMID: 30036814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Pterocarpans
• Tosyl Compounds
• Palladium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Catalysis
• Cell Line, Tumor
• Cell Survival (drug effects)
• Computer Simulation
• Female
• Humans
• Leukemia (drug therapy)
• Palladium (chemistry)
• Pterocarpans (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tosyl Compounds (chemical synthesis, chemistry, pharmacology)