Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents

Abstract

The immunosuppressant drug rapamycin, was firstly identified as a mammalian target of rapamycin (mTOR) allosteric inhibitor, and its derivatives have been successfully developed as anti-cancer drugs. Therefore, finding rapamycin derivatives with better anti-cancer activity has been proved to be an effective way to discover new targeted anti-cancer drugs. In this paper, structure modification was performed at the C-43 position of rapamycin using bioisosterism and a hybrid approach: a series of novel rapamycin-benzothiazole hybrids 4a-e, 5a-c, and 9a, b have been designed, synthesized and evaluated for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of these compounds (4a-e, 9a, b) displayed good to excellent potency against the Caski and SK-NEP-1 cell line as compared with rapamycin. Compound 9b as the most active compound showed IC 50 values of 8.3 (Caski) and 9.6 μM (SK-NEP-1), respectively. In addition, research on the mechanism showed that 9b was able to cause G1 phase arrest and induce apoptosis in the Caski cell line. Most importantly, it significantly decreased the phosphorylation of S6 ribosomal protein, p70S6K1 and 4EBP1, which indicated that 9b inhibited the cancer cell growth by blocking the mTOR pathway and may have the potential to become a new mTOR inhibitor.Key words rapamycin; benzothiazole; hybrid approach; anti-cancer activity Rapamycin, a 31-member polyketide macrolide, was discovered as a fermentation product of the Streptomyces hygroscopicus AYB-944 and FC904, best known as a potent immunosuppressive agent later.

ADMET Prediction of synthesized Heterocyclic derivatives to treat renal cancer

“…An extensive review study was carried out on heterocyclic derivatives designed, synthesized, characterized, and evaluated against renal carcinoma cell lines. The study focused on selecting potent compounds from the synthesized heterocyclic moieties such as pyrimidine [16][17][18][19][20][21][22], phthalazine [23], benzothiazole [24], Benzpyrazoline [25,26], indoline [27][28][29][30][31], benzimidazole [32], phthalazone [33], indole [34,35], quinoline [36,37], quinazoline [38] based on their IC50 value and cell inhibition (%) against renal cancer cell line such as 786-O, A-498, TK-10, UO-31, ACHN, SKNEP-1, HEK-293, CAK-1, RCC, 760-O, RXF393, SN12C and CAKi-1. Around 648 synthesized compounds were studied, and 121 potent compounds were selected.…”

“…Compounds 27-34 exhibited remarkable broad spectrum cell growth inhibition (above 90%) against various renal cancer cell lines with GI50 values ranging from 0.15-8.41 µm [23]. Compounds 35-39 containing N-methyl group on thiazole ring displayed more potent activity than Rapamycin against SKNEP-1 (renal cancer cell line) with a growth inhibition rate of 47.09-52.3% [24]. Compound 42 showed the highest inhibition activity in the VEGFR-2 Kinase assay with an IC50 value= of 44 nm [25].…”

“…Around 60% of the medications used for cancer treatment are based on heterocyclic moieties [13]. Heterocyclic compounds like pyrimidine [16][17][18][19][20][21][22], phthalazine [23], benzothiazole [24], Benzpyrazoline [25,26], indoline [27][28][29][30][31], benzimidazole [32], phthalazone [33], indole [34,35], quinoline [36,37], quinazoline [38] find application in the treatment of renal cancer. Many synthetic nitrogen heterocycles are extremely relevant to pharmacology and medicine.…”

Synthesis and anticancer activity of novel rapamycin C‐28 containing triazole moiety compounds

“…In our previous work, rapamycin was chemically modified in the position C‐43 and a number of new rapalogs with antitumor activities were obtained. Among these new rapalogs, rapamycin triazole derivative 9e and thiazole derivative 9b etc. exhibited stronger antitumor activities compared with rapamycin .…”