Novel VEGFR2 inhibitors with thiazoloquinoxaline scaffold targeting hepatocellular carcinoma with lower cardiotoxic impact.

Hepatocellular carcinoma (HCC) is a fatal tumor which is usually diagnosed at advanced stage. Molecular targeted drugs were used recently to treat HCC, however, due to serious side effects, mainly cardiotoxicity and emergence of resistance, there is demanding to explore new chemotherapeutics. 10 novel thiazoloquinoxaline derivatives coupled with different sulfonamide moieties 4(a-j) were designed and synthesized fulfilling pharmacophoric features of VEGFR-2 inhibition. Structures of all new compounds were verified via spectral and microanalytical data. After carrying in-vitro VEGFR-2 assay for compounds 4(a-j); sulfapyridine and sulfamethoxazole derivatives 4d and 4f showed potential inhibitory effect [61.04 and 83.35 nM], respectively, comparable to standard sorafenib [51.41 nM]. Both were then further evaluated for their cytocidal activity against HepG2 cell-line and against myocardium cells using H9C2 cell-line. As a result, only sulfapyridine derivative 4d exhibited a significant inhibition of HepG2 cells viability [IC50 = 4.31 µM]. Furthermore, it showed relatively lower cytotoxic impact against normal H9C2 myocardium cells [IC50, 33.47 µM] compared to that of sorafenib [IC50, 98.07 µM]. In-vivo study was carried out to determine myocardium safety of compound 4d on irradiated mice (8 Gy). In-vivo results of sulfapyridine derivative 4d showed normal cardiac enzyme function (CK) and serum catalase activity with significant reductions in LDH, cardiac TNF-α and caspase-9 levels, alongside with its efficacy in suppressing the expression of hepatic VEGF. In conclusion, sulfapyridine derivative 4d could be considered a promising candidate as VEGFR-2 inhibitor with less myocardium side effect.

Pyrazole-sulfonamide scaffold featuring dual-tail strategy as apoptosis inducers in colon cancer.

Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with IC50s' of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. Both compounds were less cytotoxic than the reference drug on normal epithelial cell. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, molecular docking of compounds 3 and 11 into the active site of CA IX confirmed in vitro inhibitory activity for both compounds.

Anti-inflammatory and analgesic effect of LD-RT and some novel thiadiazole derivatives through COX-2 inhibition.

Generally, highly selective COX-2 inhibitors cause cardiovascular side effects. Celecoxib is the highly marketed coxib, so there is still a need for the synthesis of COX-2 inhibitors with less adverse effects. Moreover, low-dose radiotherapy (LD-RT) is clinically used for the treatment of inflammatory diseases. The present study aimed to investigate the analgesic and anti-inflammatory activity of a novel series of 1,3,4-thiadiazole derivatives alone or combined with LD-RT with a single dose of 0.5 Gy. Initially, in vitro COX-1/COX-2 inhibition assays were performed, identifying the sulfonamide-containing compounds 5-10 as the most potent candidates, with IC50 values in the range of 0.32-0.37 µM and the highest selectivity indices. These compounds and celecoxib were subjected to in vivo examination after their safety was assessed through the acute toxicity test. Treatment with compounds 5-10 inhibited carrageenan-induced edema by nearly 47-56%, which was nearly equivalent to celecoxib. Compounds 7 and 8 and celecoxib showed an analgesic activity of 64.15%, 49.05%, and 84.90%, respectively, whereas compounds 5, 6, 9, and 10 did not show any analgesic activity unless combined with LD-RT. Ulcerogenic activity, histological paw examination, and docking studies were performed. Compounds 5-10 were nearly similar to celecoxib, showing normal histological features with no ulcerogenic activity.