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

[Display omitted] •Palladium-catalyzed azaarylation reaction is the key step for the synthesis of N-tosyl-carbapterocarpans.•Compounds 5b and 7 present higher potencies and the best selectivity indices for leukemia cell lines.•Compound 5b is the most promising prototype for targeting breast cancer c...

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Published in:	Bioorganic chemistry Vol. 80; pp. 585 - 590
Main Authors:	Mendes, Joseane A., Salustiano, Eduardo J., Pires, Carulini de S., Oliveira, Thaís, Barcellos, Julio C.F., Cifuentes, Jhonny M.C., Costa, Paulo R.R., Rennó, Magdalena N., Buarque, Camilla D.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-10-2018
Subjects:	Cancer Druglikeness Molecular descriptors Multidrug resistant phenotype (MDR) N-tosyl-carbapterocarpans N-tosyl-carbapterocarpans Molecular descriptors CMRUDJCDJDEHFQ-FYYLOGMGSA-N AABHTRGBALOPLD-OFNKIYASSA-N Druglikeness CSYLMVCMPNCBMW-NFBKMPQASA-N UUNISZPPBPZRLP-NFBKMPQASA-N Cancer Multidrug resistant phenotype (MDR)
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Summary:	[Display omitted] •Palladium-catalyzed azaarylation reaction is the key step for the synthesis of N-tosyl-carbapterocarpans.•Compounds 5b and 7 present higher potencies and the best selectivity indices for leukemia cell lines.•Compound 5b is the most promising prototype for targeting breast cancer cells.•The N-tosyl group is fundamental for the biological activity. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0045-2068 1090-2120
DOI:	10.1016/j.bioorg.2018.07.004