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Evaluation of Anti‐Cancer Activity of Simplified Staurosporine Analogs
Author(s) -
Neerukonda Namita,
Pelky Erin T.,
Mowery Patricia
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.766.14
Subject(s) - staurosporine , protein kinase c , chemistry , indole test , apoptosis , kinase , cancer cell , ic50 , enzyme , biochemistry , cytotoxicity , structure–activity relationship , stereochemistry , cancer , pharmacology , cancer research , in vitro , biology , genetics
Protein Kinase C (PKC) is a family of enzymes involved in numerous cellular functions, such as proliferation, apoptosis, morphological changes, and migration. Overexpression of PKC has been implicated in numerous diseases, including cancer, and thus PKC is a promising therapeutic target. Staurosporine, a natural bacterial compound, was the first indolocarbazole PKC inhibitor identified, however it is too promiscuous for clinical applications. Simplified staurosporine analogs have increased specificity and have been tested for therapeutic potential. The Pelkey research group has synthesized numerous simplified derivatives of staurosporine, which have promising structural features for inhibiting PKC; the analogs contain a central 3‐pyrrolin‐2‐one core with different methoxyphenyl and/or indole substituents. The Mowery research group has tested the cytotoxicity of the analogs on human myeloid U‐937 cells using a MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay to determine IC 50 values along with direct cell count confirmations. We learned that flexibility of the molecule was critical, as cyclization eliminated or significantly reduced activity. Three analogs were found to have low uM IC 50 values representing two structurally related but distinct classes: 3‐pyrrolin‐2‐one cores with C4 substitution (methoxyaryl) and C3 substitution (either indole or an additional methoxyaryl). Studies are currently underway to determine if the most potent compounds induce toxicity via apoptosis and the target(s) of the two structural classes. Overall, this work provides guidance to better understand structure‐activity relationships for inducing anti‐cancer activity in diaryl heterocyclic scaffolds.