Design, Synthesis of Novel Tetrandrine-14-l-Amino Acid and Tetrandrine-14-l-Amino Acid-Urea Derivatives as Potential Anti-Cancer Agents

Abstract

Tetrandrine, a dibenzyltetrahydroisoquinoline alkaloid isolated from the root of the traditional Chinese medicinal plant Stephania tetrandra S. Moore, a member of the Menispermaceae, showed anti-cancer activity by inhibiting cell proliferation, preventing cell cycle progress and induction of cell death and autophagy. In this study, twelve tetrandrine-l-amino acid derivatives and twelve tetrandrine-14-l-amino acid-urea derivatives were designed and synthesized, using C14-aminotetrandrine as raw material. Then the preliminary in vitro anti-cancer activities of these derivatives against human breast cancer cell line MDA-MB-231, human leukemia cell lines HEL and K562 were evaluated. The in vitro cytotoxicity results showed that these derivatives exhibited potent inhibitory effects on cancer cell growth, and the primary structure-activity relationships were evaluated. Notably, compound 3f exhibited satisfactory anticancer activity against all three cancer cell lines, especially the HEL cell line, with the IC50 value of 0.23 µM. Further research showed that 3f could induce G1/S cycle arrest and apoptosis in a dose- and time- dependent manner on the leukemia cell line HEL. The results suggested that 3f may be used as a potential anti-cancer agent for human leukemia.

Progress on structural modification of Tetrandrine with wide range of pharmacological activities

“…Tet has good antitumor effects against a variety of solid tumors and leukemias, including: nasopharyngeal carcinoma ( Wang et al, 2020a ),bladder cancer ( Li et al, 2011a ),triple-negative breast cancer ( Yuan et al, 2018 ),lung cancer ( Chen et al, 2018 ),liver cancer ( Chen et al, 2018 ; Zhang et al, 2018 ),gastric cancer ( Wei et al, 2007 )and leukemia ( Hu et al, 2020 ), etc. It inhibits tumor cell migration and invasion, enhances radiosensitivity, induces apoptosis, inhibits tumor cell proliferation and tumor growth, induces autophagy, inhibits vascular regeneration, and reverses tumor multidrug resistance.…”

RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy

“…From 2005 to 2020, the total number of deaths due to cancer in China increased by 21.6% to 2 397 772, and the mortality rate and years of life lost increased by 5.0% to 56 598 975 5 . Despite major advances in the treatment of cancer with various therapies such as surgery, radiotherapy and chemotherapy, the prognosis for most cancer patients is still poor 2,6 . Therefore, the exploration of new molecular mechanisms affecting cancer is important for establishing new therapeutic options.…”

“…5 Despite major advances in the treatment of cancer with various therapies such as surgery, radiotherapy and chemotherapy, the prognosis for most cancer patients is still poor. 2,6 Therefore, the exploration of new molecular mechanisms affecting cancer is important for establishing new therapeutic options.…”

“…Cancer is one of the major diseases threatening human health, 1 , 2 and the incidence and mortality have increased rapidly in the past 20 years. 3 There are an average of 12 000 new cancer cases and 10 000 cancer deaths every day, which corresponds to an average of about 7500 cancer deaths every year.…”