Synthesis and in-vitro study of pyrimidine-phthalimide hybrids as VEGFR-2 inhibitors with Anti-proliferative activity - supplementary material

Highlights:

1. Synthesis of different thalidomide analogues starting from 6-aminouracil through the attachment of phthalimide and 2,4-dichloropyrimidine.

2. In-silico ADMET studies showed that compounds represent good oral bioavailable drug candidates that can pass the gut wall but not the blood - brain barrier with any potential side effects to the liver.

3. All compounds were non-mutagenic and non-carcinogenic using an in-silico toxicity prediction tool.

4. Most of the compounds demonstrated good oral bioavailability and good gastrointestinal absorption with no possible adverse effects on the liver or CNS. In addition.

5. Compounds showed anti-proliferative activity against four cell lines Hepatocellular carcinoma (HEPG-2), Mammary gland breast cancer (MCF-7), Colorectal carcinoma Colon cancer (HCT-116), and Human prostate cancer (PC-3) compared to Thalidomide and Doxorubicin.7d, 5f, 5g and 6 showed weak anti-proliferative activity. 7a, 5b, 5d and 5e showed the moderate anti-proliferative activity while 4,7c, 5a and 5c showed high anti-proliferative activity with selective cytotoxicity.

6. 4, 7c, 5a and 5c showed in-vitro inhibitory activity of VEGFR-2 and were capable of binding at VEGFR-2 binding site in an inhibitory mode. Flow-cytometric analysis of cell cycle distribution and apoptosis on MCF-7 showed that 7c arrested the cell cycle at the S phase and increased the ratio of total apoptotic cells by 50 folds (37.68%) compared to 0.75% in untreated cells.