New thiazolidine-2,4-diones as potential anticancer agents and apoptotic inducers targeting VEGFR-2 kinase: Design, synthesis, in silico and in vitro studies

被引：5

作者：

Elkady, Hazem ^{[1
]}

Mahdy, Hazem A. ^{[1
]}

Taghour, Mohammed S. ^{[1
]}

Dahab, Mohammed A. ^{[1
]}

Elwan, Alaa ^{[1
]}

Hagras, Mohamed ^{[2
]}

Hussein, Mona H. ^{[3
]}

Ibrahim, Ibrahim M. ^{[4
]}

Husein, Dalal Z. ^{[5
]}

Elkaeed, Eslam B. ^{[6
]}

Alsfouk, Aisha A. ^{[7
]}

Metwaly, Ahmed M. ^{[8
,9
]}

Eissa, Ibrahim H. ^{[1
]}

机构：

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

[2] Al Azhar Univ, Coll Pharm, Dept Pharmaceut Organ Chem, Cairo 11884, Egypt

[3] Al Azhar Univ, Coll Pharm Girls, Dept Pharmaceut Organ Chem, Cairo, Egypt

[4] Cairo Univ, Fac Sci, Biophys Dept, Giza 12613, Egypt

[5] New Valley Univ, Fac Sci, Chem Dept, El Kharja 72511, Egypt

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

[7] Princess Nourah Bint Abdulrahman Univ, Coll Sci, Dept Biol, POB 84428, Riyadh 11671, Saudi Arabia

[8] Al Azhar Univ, Fac Pharm Boys, Pharmacognosy & Med Plants Dept, Cairo 11884, Egypt

[9] City Sci Res & Technol Applicat SRTA City, Biopharmaceut Prod Res Dept, Genet Engn & Biotechnol Res Inst, Alexandria 21934, Egypt

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2024年 / 1868卷 / 06期

关键词：

Apoptosis; Anti-proliferative; VEGFR-2; Thiazolidine-2; 4-dione; MD simulations; Docking; DFT; BIOLOGICAL EVALUATION; MOLECULAR DOCKING; CELL-LINES; INHIBITORS; DERIVATIVES; DISCOVERY; ADMET; ANGIOGENESIS; SIMULATIONS; PREDICTION;

D O I：

10.1016/j.bbagen.2024.130599

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：

Background: VEGFR-2 has emerged as a prominent positive regulator of cancer progression. Aim: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. Methods: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. Results: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC 50 value of 0.066 mu M. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC 50 values ranging from 0.04 to 4.71 mu M, relative to sorafenib (IC 50 = 2.24 +/- 0.06 and 3.17 +/- 0.01 mu M against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. Conclusion: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer.

引用

页数：25

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