2. Academic Validation
  3. Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents

Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents

  • Eur J Med Chem. 2022 Nov 5:241:114651. doi: 10.1016/j.ejmech.2022.114651.
Meng-Xue Wei 1,  Yi-Xuan Zhou 2,  Mengxia Lin 3,  Jun Zhang 2,  Xuanrong Sun 4
Affiliations

Affiliations

  • 1 State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, National Demonstration Center for Experimental Chemistry Education, College of Chemistry and Chemical Engineering, Ningxia University, 489 Helanshan West Road, Yinchuan, 750021, China; Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. Electronic address: weimengxue@nxu.edu.cn.
  • 2 State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, National Demonstration Center for Experimental Chemistry Education, College of Chemistry and Chemical Engineering, Ningxia University, 489 Helanshan West Road, Yinchuan, 750021, China.
  • 3 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China.
  • 4 Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China. Electronic address: sunxr@zjut.edu.cn.
PMID: 35963130 DOI: 10.1016/j.ejmech.2022.114651
Abstract

A series of novel rhein-piperazine-dithiocarbamate hybrids 3 were efficiently synthesized from rhein through a catalyst-free and one-pot, three-step sequence involving chlorination and N-acylation followed by dithiocarbamate formation. Hybrids 3 were evaluated for their in vitro cytotoxic potency by MTT assay against several human Cancer and non-cancer cells. Five of the hybrids were more cytotoxic to human lung Cancer cell line A549 than the parent rhein and the reference, cytarabine (CAR). Structure-activity relationship (SAR) analysis indicated that cytotoxicity was significantly enhanced when ester groups were incorporated into the hybrids (3h-j). In particular, hybrid 3h (IC50 = 10.93 μg/mL), containing a long-chain alkyl ester, was the most potent compound toward A549 tumor cells, being 7- and 5-fold more toxic than rhein (IC50 = 77.11 μg/mL) and CAR (IC50 = 49.27 μg/mL), respectively. Additionally, hybrid 3h was less toxic to the corresponding normal human lung fibroblast cell line, WI-38, with a higher selectivity index (SI, WI-38/A549 ≈ 5) than doxorubicin (DOX, SI ≈ 0), CAR (SI ≈ 2) and rhein (SI ≈ 1). Furthermore, hybrid 3h displayed more toxicity against four types of lung Cancer cells (A549, Calu-1, PC-9, and H460; IC50 = 10.81-23.78 μg/mL) than against six Other types of Cancer cells (Huh-7, 786-O, HCT116, Hela, SK-BR-3, and SK-OV-3; IC50 = 23.85-51.98 μg/mL). Further mechanistic studies showed that hybrid 3h induced Apoptosis in a concentration-dependent manner in human lung adenocarcinoma cell line PC-9. In vivo safety studies showed that hybrid 3h had no acute toxicity to the major organs of mice and did not lead to blood biochemical index changes. Our results exhibit prominent anti-cancer cell inhibition ability and no obvious systemic toxicity to normal organs, indicating that hybrid 3h has promising potential for further applications in anti-lung Cancer drug development.

Keywords

Anti-cancer drugs; Biological activity; Dithiocarbamate; Rhein; Safety evaluation; Synthesis.

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