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一种新型苯并香豆素-二苯乙烯杂合体作为 DNA 连接酶 I 抑制剂，在乳腺癌模型中具有体外和体内抗肿瘤活性。

A Novel Benzocoumarin-Stilbene Hybrid as a DNA ligase I inhibitor with in vitro and in vivo anti-tumor activity in breast cancer models.

机构信息

Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India.

Department of Chemistry Govt. Raza Post Graduate College, Rampur, 244901, India.

出版信息

Sci Rep. 2017 Sep 6;7(1):10715. doi: 10.1038/s41598-017-10864-3.

DOI:10.1038/s41598-017-10864-3
PMID:28878282
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5587642/
Abstract

Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.

摘要

现有的癌症疗法常常伴随着耐药性和毒性，这导致了预后不良和癌症的复发。这就需要针对现有和新的细胞靶点，识别和开发新的治疗方法。在这项研究中，合成了一类新型苯并香豆素-二苯乙烯杂化分子，并对其针对各种癌细胞系的增殖活性进行了评估，随后在癌症的小鼠模型中进行了体内抗肿瘤活性研究。在该系列中最有前途的分子，即（E）-4-（3,5-二甲氧基苯乙烯基）-2H-苯并[h]色烯-2-酮（19），在乳腺癌细胞系（MDA-MB-231 和 4T1）中表现出最大的增殖抑制活性，并减少了体内 4T1 细胞诱导的同基因小鼠乳腺癌模型中的肿瘤大小。通过各种生化、细胞生物学和生物物理方法对化合物 19 的机制研究表明，该化合物与并抑制人 DNA 连接酶 I 酶活性，这可能是肿瘤生长显著减少的原因，并且可能成为针对乳腺癌的下一代有前途的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/d44caab6531f/41598_2017_10864_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/75917e2dfbec/41598_2017_10864_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/d44caab6531f/41598_2017_10864_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/bdfe964568f3/41598_2017_10864_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/14cccd602998/41598_2017_10864_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/e0ba929480e9/41598_2017_10864_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/5d52d22e31f4/41598_2017_10864_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/82f48141a82a/41598_2017_10864_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/1d554466d47b/41598_2017_10864_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/9cb6ac57db15/41598_2017_10864_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/20e95bdefdca/41598_2017_10864_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/75917e2dfbec/41598_2017_10864_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ddd/5587642/d44caab6531f/41598_2017_10864_Fig10_HTML.jpg

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