Synthesis of novel, peptidic kinase inhibitors with cytostatic/cytotoxic activity

Wiktor Szymanski; Magdalena Zwolinska; Szymon Klossowski; Izabela Mlynarczuk-Bialy; Lukasz Bialy; Tadeusz Issat; Jacek Malejczyk; Ryszard Ostaszewski

doi:10.1016/j.bmc.2014.01.005

Synthesis of novel, peptidic kinase inhibitors with cytostatic/cytotoxic activity

Wiktor Szymanski, Magdalena Zwolinska, Szymon Klossowski, Izabela Mlynarczuk-Bialy, Lukasz Bialy, Tadeusz Issat, Jacek Malejczyk, Ryszard Ostaszewski^*

^*Corresponding author for this work

Synthetic Organic Chemistry

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

14 Citations (Scopus)

Abstract

The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway. (C) 2014 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	1773-1781
Number of pages	9
Journal	Bioorganic & Medicinal Chemistry
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2014.01.005
Publication status	Published - 1-Mar-2014

Keywords

Peptidomimetics
Biotransformations
Cytostatic/cytotoxic effect
Kinase inhibitors
ALPHA-AMINO-ACIDS
PHASE-I
RAS
PROTEASOME
PATHWAY
GROWTH
CELLS

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title = "Synthesis of novel, peptidic kinase inhibitors with cytostatic/cytotoxic activity",

abstract = "The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway. (C) 2014 Elsevier Ltd. All rights reserved.",

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T1 - Synthesis of novel, peptidic kinase inhibitors with cytostatic/cytotoxic activity

AU - Szymanski, Wiktor

AU - Zwolinska, Magdalena

AU - Klossowski, Szymon

AU - Mlynarczuk-Bialy, Izabela

AU - Bialy, Lukasz

AU - Issat, Tadeusz

AU - Malejczyk, Jacek

AU - Ostaszewski, Ryszard

PY - 2014/3/1

Y1 - 2014/3/1

N2 - The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway. (C) 2014 Elsevier Ltd. All rights reserved.

AB - The utility of a novel, chemoenzymatic procedure for the stereocontrolled synthesis of small peptides is presented in the preparation and structure optimisation of dipeptides with cytostatic/cytotoxic activity. The method uses Passerini multicomponent reaction for the preparation of racemic scaffold which is then enantioselectively hydrolysed by hydrolytic enzymes. Products of these transformations are further functionalised towards title compounds. Both activity and selectivity towards tumor cells is optimised. Final compound is shown to be an inhibitor of the protein kinase signaling pathway. (C) 2014 Elsevier Ltd. All rights reserved.

KW - Peptidomimetics

KW - Biotransformations

KW - Cytostatic/cytotoxic effect

KW - Kinase inhibitors

KW - ALPHA-AMINO-ACIDS

KW - PHASE-I

KW - RAS

KW - PROTEASOME

KW - PATHWAY

KW - GROWTH

KW - CELLS

U2 - 10.1016/j.bmc.2014.01.005

DO - 10.1016/j.bmc.2014.01.005

M3 - Article

SN - 0968-0896

VL - 22

SP - 1773

EP - 1781

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

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