Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

被引：43

作者：

Elwan, Alaa ^{[1
]}

Abdallah, Abdallah E. ^{[1
]}

Mahdy, Hazem A. ^{[1
]}

Dahab, Mohammed A. ^{[1
]}

Taghour, Mohammed S. ^{[1
]}

Elkaeed, Eslam B. ^{[2
]}

Mehany, Ahmed B. M. ^{[3
]}

Nabeeh, Ahmed ^{[3
]}

Adel, Mohammed ^{[3
]}

Alsfouk, Aisha A. ^{[4
]}

Elkady, Hazem ^{[1
]}

Eissa, Ibrahim H. ^{[1
]}

机构：

[1] Al Azhar Univ, Fac Pharm Boys, Pharmaceut Med Chem & Drug Design Dept, Cairo 11884, Egypt

[2] AlMaarefa Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh 13713, Saudi Arabia

[3] Al Azhar Univ, Fac Sci Boys, Zool Dept, Cairo 11884, Egypt

[4] Princess Nourah Bint Abdulrahman Univ, Coll Pharm, Dept Pharmaceut Sci, Riyadh 11671, Saudi Arabia

来源：

MOLECULES | 2022年 / 27卷 / 15期

关键词：

anticancer; benzoxazole; molecular modeling; VEGFR-2; kinase; ENDOTHELIAL GROWTH-FACTOR; ANTICANCER AGENTS; IN-SILICO; COLORECTAL-CANCER; MOLECULAR DOCKING; DERIVATIVES; ANGIOGENESIS; EXPRESSION; DISCOVERY; RECEPTORS;

D O I：

10.3390/molecules27155047

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC50 values of 3.43, 2.79, and 2.43 mu M against the aforementioned cancer cell lines, respectively, compared to IC50 values of 4.21, 5.30, and 3.40 mu M reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC50 value of 0.0554 mu M compared to sorafenib (0.0782 mu M). In addition, compound 8h revealed excellent cytotoxic effects with IC50 values of 3.53, 2.94, and 2.76 mu M against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC50 values of 0.0579 and 0.0741 mu M, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-alpha (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.

引用

页数：24

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