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Synthesis of montbretin A analogues yields potent competitive inhibitors of human pancreatic ?-amylase.

ABSTRACT: Simplified analogues of the potent human amylase inhibitor montbretin A were synthesised and shown to bind tightly, K I = 60 and 70 nM, with improved specificity over medically relevant glycosidases, making them promising candidates for controlling blood glucose. Crystallographic analysis confirmed similar binding modes and identified new active site interactions.

SUBMITTER: Tysoe CR

PROVIDER: S-EPMC7069248 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Synthesis of montbretin A analogues yields potent competitive inhibitors of human pancreatic α-amylase.

Tysoe Christina R CR Caner Sami S Calvert Matthew B MB Win-Mason Anna A Brayer Gary D GD Withers Stephen G SG

Chemical science 20191018 48

Simplified analogues of the potent human amylase inhibitor montbretin A were synthesised and shown to bind tightly, <i>K</i> <sub>I</sub> = 60 and 70 nM, with improved specificity over medically relevant glycosidases, making them promising candidates for controlling blood glucose. Crystallographic analysis confirmed similar binding modes and identified new active site interactions. ...[more]

PMID: 32206255

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Project description:Upregulation of cathepsin L in a variety of tumors and its ability to promote cancer cell invasion and migration through degradation of the extracellular matrix suggest that cathepsin L is a promising biological target for the development of anti-metastatic agents. Based on encouraging results from studies on benzophenone thiosemicarbazone cathepsin inhibitors, a series of fourteen benzoylbenzophenone thiosemicarbazone analogues were designed, synthesized, and evaluated for their inhibitory activity against cathepsins L and B. Thiosemicarbazone inhibitors 3-benzoylbenzophenone thiosemicarbazone 1, 1,3-bis(4-fluorobenzoyl)benzene thiosemicarbazone 8, and 1,3-bis(2-fluorobenzoyl)-5-bromobenzene thiosemicarbazone 32 displayed the greatest potency against cathepsin L with low IC50 values of 9.9 nM, 14.4 nM, and 8.1 nM, respectively. The benzoylbenzophenone thiosemicarbazone analogues evaluated were selective in their inhibition of cathepsin L compared to cathepsin B. Thiosemicarbazone analogue 32 inhibited invasion through Matrigel of MDA-MB-231 breast cancer cells by 70% at 10 ?M. Thiosemicarbazone analogue 8 significantly inhibited the invasive potential of PC-3ML prostate cancer cells by 92% at 5 ?M. The most active cathepsin L inhibitors from this benzoylbenzophenone thiosemicarbazone series (1, 8, and 32) displayed low cytotoxicity toward normal primary cells [in this case human umbilical vein endothelial cells (HUVECs)]. In an initial in vivo study, 3-benzoylbenzophenone thiosemicarbazone (1) was well-tolerated in a CDF1 mouse model bearing an implanted C3H mammary carcinoma, and showed efficacy in tumor growth delay. Low cytotoxicity, inhibition of cell invasion, and in vivo tolerability are desirable characteristics for anti-metastatic agents functioning through an inhibition of cathepsin L. Active members of this structurally diverse group of benzoylbenzophenone thiosemicarbazone cathepsin L inhibitors show promise as potential anti-metastatic, pre-clinical drug candidates.

Dataset Information

Synthesis of montbretin A analogues yields potent competitive inhibitors of human pancreatic ?-amylase.

Publications

Synthesis of montbretin A analogues yields potent competitive inhibitors of human pancreatic α-amylase.

Similar Datasets

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