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Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

ABSTRACT: The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC₅₀ values between 2.81-29.6 μg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four out of five examined cell lines and was 14 times more selective against MRC5. The flow cytometric analysis confirmed the induction of apoptotic cell death by this compound against HUVEC and MCF-7 cells. In addition, 11n caused sub-G1 phase arrest in the cell cycle arrest. Besides, this compound induced anti-angiogenesis in CAM assay and increased the level of caspase-3 by 5.2 fold. The western-blot analysis of the most active compound, 11n, revealed the inhibition of VEGFR-2 phosphorylation. Molecular docking study also showed the important interactions for compound 11n.

SUBMITTER: Motahari R

PROVIDER: S-EPMC9188586 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

Motahari Rasoul R Boshagh Mohammad Amin MA Moghimi Setareh S Peytam Fariba F Hasanvand Zaman Z Oghabi Bakhshaiesh Tayebeh T Foroumadi Roham R Bijanzadeh Hamidreza H Firoozpour Loghman L Khalaj Ali A Esmaeili Rezvan R Foroumadi Alireza A

Scientific reports 20220611 1

The novel derivatives of tetrahydropyridothienopyrimidine-based compounds have been designed and efficiently synthesized with good yields through seven steps reaction. The anticancer activity of compounds 11a-y has been evaluated against MCF-7, PC-3, HEPG-2, SW-480, and HUVEC cell lines by MTT assay. The target compounds showed IC<sub>50</sub> values between 2.81-29.6 μg/mL and were compared with sorafenib as a reference drug. Among them, compound 11n showed high cytotoxic activity against four ...[more]

PMID: 35690595

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Project description:BackgroundChrysin (5,7-dihydroxyflavone) is a widely distributed natural flavonoid found in many plant extracts, honey and propolis. Several studies revealed that chrysin possesses multiple biological activities including anti-cancer effects. It has been established that activation of apoptosis is the key molecular mechanism responsible for the cytotoxic potential of chrysin. The objective of this study was to design and synthesize potent chrysin analogues as potential cytotoxic agents.MethodsA series of chrysin derivatives (3a-m) bearing N'-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and evaluated for their antiproliferative activity against two human breast cancer cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected compounds were tested for their ability to induce apoptosis through caspase 3/7 activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3.ResultsCompounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in good yields upon treatment of hydrazide 5 with different aliphatic and aromatic aldehydes. Most of the synthesized compounds demonstrated moderate-to-good activity against both cell lines. The cytotoxicity results revealed the importance of lipophilic moieties at C-4 position of ring D in imparting the cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent was found to be the most active among the synthesized compounds with IC50 3.3 µM against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential of compound 3e is comparable to that of the well-known anti-cancer agent doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and dimethylamino (3j) exhibited good cytotoxicity with IC50 <6.5 µM against MDA-MB-231 and <12 µM against MCF-7. Selected compounds were able to induce apoptosis in MDA-MB-231 cells as indicated by caspase-3 and/or -7 activation.ConclusionOur results show that the newly designed chrysin derivatives exert anticancer activity in human breast cancer cell lines, MDA-MB-231 and MCF-7. Therefore, they can be considered as leads for further development of more potent and selective cytotoxic agents.

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Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

Publications

Design, synthesis and evaluation of novel tetrahydropyridothienopyrimidin-ureas as cytotoxic and anti-angiogenic agents.

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