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Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. / Krasavin, Mikhail; Gureyev, Maxim A.; Dar'in, Dmitry; Bakulina, Olga; Chizhova, Maria; Lepikhina, Anastasia; Novikova, Daria; Grigoreva, Tatyana; Ivanov, Gleb; Zhumagalieva, Aisulu; Garabadzhiu, Alexander V.; Tribulovich, Vyacheslav G.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 9, 15.05.2018, p. 2651-2673.

Research output: Contribution to journal › Article › peer-review

Harvard

Krasavin, M, Gureyev, MA, Dar'in, D, Bakulina, O, Chizhova, M, Lepikhina, A, Novikova, D, Grigoreva, T, Ivanov, G, Zhumagalieva, A, Garabadzhiu, AV & Tribulovich, VG 2018, 'Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction', Bioorganic and Medicinal Chemistry, vol. 26, no. 9, pp. 2651-2673. https://doi.org/10.1016/j.bmc.2018.04.036

APA

Krasavin, M., Gureyev, M. A., Dar'in, D., Bakulina, O., Chizhova, M., Lepikhina, A., Novikova, D., Grigoreva, T., Ivanov, G., Zhumagalieva, A., Garabadzhiu, A. V., & Tribulovich, V. G. (2018). Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. Bioorganic and Medicinal Chemistry, 26(9), 2651-2673. https://doi.org/10.1016/j.bmc.2018.04.036

Vancouver

Krasavin M, Gureyev MA, Dar'in D, Bakulina O, Chizhova M, Lepikhina A et al. Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. Bioorganic and Medicinal Chemistry. 2018 May 15;26(9):2651-2673. https://doi.org/10.1016/j.bmc.2018.04.036

Author

Krasavin, Mikhail ; Gureyev, Maxim A. ; Dar'in, Dmitry ; Bakulina, Olga ; Chizhova, Maria ; Lepikhina, Anastasia ; Novikova, Daria ; Grigoreva, Tatyana ; Ivanov, Gleb ; Zhumagalieva, Aisulu ; Garabadzhiu, Alexander V. ; Tribulovich, Vyacheslav G. / Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 9. pp. 2651-2673.

BibTeX

@article{5349f06b1b5a457f8188d1e36b4ef78f,
title = "Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction",
abstract = "Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53+ cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53+ H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53+/+ HCT116 cells in much lower concentration range compared to p53−/− HCT116 cells.",
keywords = "Antiproliferative activity, Apoptosis induction, Protein-protein interactions, Transcription factor, Tumor suppressor, Virtual library, MUTANT, MDM2-P53 INTERACTION, PROTEIN-PROTEIN INTERACTION, ACTIVATORS, CANCER, DISCOVERY, P53, POTENT, SMALL-MOLECULE INHIBITORS, DIVERSITY",
author = "Mikhail Krasavin and Gureyev, {Maxim A.} and Dmitry Dar'in and Olga Bakulina and Maria Chizhova and Anastasia Lepikhina and Daria Novikova and Tatyana Grigoreva and Gleb Ivanov and Aisulu Zhumagalieva and Garabadzhiu, {Alexander V.} and Tribulovich, {Vyacheslav G.}",
year = "2018",
month = may,
day = "15",
doi = "10.1016/j.bmc.2018.04.036",
language = "English",
volume = "26",
pages = "2651--2673",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier",
number = "9",

}

RIS

TY - JOUR

T1 - Design, in silico prioritization and biological profiling of apoptosis-inducing lactams amenable by the Castagnoli-Cushman reaction

AU - Krasavin, Mikhail

AU - Gureyev, Maxim A.

AU - Dar'in, Dmitry

AU - Bakulina, Olga

AU - Chizhova, Maria

AU - Lepikhina, Anastasia

AU - Novikova, Daria

AU - Grigoreva, Tatyana

AU - Ivanov, Gleb

AU - Zhumagalieva, Aisulu

AU - Garabadzhiu, Alexander V.

AU - Tribulovich, Vyacheslav G.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53+ cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53+ H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53+/+ HCT116 cells in much lower concentration range compared to p53−/− HCT116 cells.

AB - Five lactam chemotypes amenable by the Castagnoli-Cushman reaction of imines and cyclic anhydrides have been investigated for their ability to activate p53 tumor suppressing transcription factor thus induce apoptosis in p53+ cancer cells. A virtual library of 1.07 million chemically diverse compounds based on these scaffolds was subjected to in silico screening first. The compounds displaying high docking score were visually prioritized to identify the best-fitting compounds, i. e. the ones which adequately mimic the interactions of clinical candidate inhibitor Nutlin-3a. These 38 compounds were synthesized and tested for apoptosis induction in p53+ H116 cancer cells to identify 9 potent apoptosis-inducers (two of them exceeding the activity of Nutlin-3a) which belonged to four different chemotypes. The activation of p53 involved in the proapoptotic activity observed was supported by effective induction of EGFP expression in human osteocarcinoma U2OS-pLV reporter cell line. Moreover, the two most potent apoptosis inducers displayed antiproliferative profile identical to several known advanced p53 activators: they inhibited the growth of p53+/+ HCT116 cells in much lower concentration range compared to p53−/− HCT116 cells.

KW - Antiproliferative activity

KW - Apoptosis induction

KW - Protein-protein interactions

KW - Transcription factor

KW - Tumor suppressor

KW - Virtual library

KW - MUTANT

KW - MDM2-P53 INTERACTION

KW - PROTEIN-PROTEIN INTERACTION

KW - ACTIVATORS

KW - CANCER

KW - DISCOVERY

KW - P53

KW - POTENT

KW - SMALL-MOLECULE INHIBITORS

KW - DIVERSITY

UR - http://www.scopus.com/inward/record.url?scp=85046163387&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2018.04.036

DO - 10.1016/j.bmc.2018.04.036

M3 - Article

AN - SCOPUS:85046163387

VL - 26

SP - 2651

EP - 2673

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 9

ER -

ID: 34631546