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Design, Synthesis, Anticancer Properties and In Silico Evaluation of C(4) N ‐Heteroaryl 4 H ‐Chromenes
Author(s) -
Prakash Rao H. Surya,
Adigopula Lakshmi Narayana,
Ramalingam Gunasundari,
Lone Javeed Ahmed,
Ramadas Krishna
Publication year - 2018
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201802270
Subject(s) - podophyllotoxin , chemistry , pharmacophore , in silico , stereochemistry , cancer cell lines , combinatorial chemistry , in vivo , cancer cell , biochemistry , cancer , biology , genetics , microbiology and biotechnology , gene
The C(4) N‐heteroaryl 2‐amino‐3‐nitro‐4 H ‐chromenes are podophyllotoxin (POD) mimics as they possess the pharmacophore features of the anticancer natural product. We have achieved a facile synthesis of several such 4 H ‐chromenes by substitution of C(4) SMe in N ‐alkyl 4‐(methylthio)‐3‐nitro‐4 H ‐chromen‐2‐amines with heteroaromatic amines like 2‐aminopyridines and 2‐aminopyrimidines. Resulting 4 H ‐chromenes were evaluated for anticancer activity against prostate and lung cancer cell lines. Two of the 4 H ‐chromenes showed significant anti‐cancer activity, even better than POD. Both of them were non‐toxic towards normal cell‐lines. In silico ADMET studies revealed drug‐likeliness of all the 4 H ‐chromenes. Molecular docking studies with αβ tubulin concurred with in vivo results and revealed that the 4 H ‐chromenes bind to the active site of POD. Molecular dynamics simulation studies on the complexes of αβ tubulin with the two best 4 H ‐chromenes revealed high stability. Overall, our studies revealed that the two 4 H ‐chromenes could act as lead compounds for further development of potent anticancer drugs.