Research paperDesign and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity
Graphical abstract
Introduction
Cancer is a serious threat to human health and become the second major cause of human death after cardiovascular disease [1]. About 7 million people each year died of various tumors around the world [2]. Therefore, there is an emergent need to develop novel anticancer agents with lower toxicity and higher efficacy. Natural products are an important source of existing drugs and should play a key role in the discovery of new anticancer drugs [3], [4], [5]. Indeed, since 1981about 50% of the new drugs directly or indirectly derived from natural products [6]. About 2/3 of antineoplastic drugs came from natural products [7], [8]. Among these are paclitaxel [9], camptothecin [10], vinblastine [11], podophyllotoxin [12] and epothilone, which commonly used the treatment of various tumors [13], [14]. As an important part of the history of Chinese civilization, the traditional Chinese medicine (TCM) has been used for thousands of years for treatment of diseases. Rich natural medicine resources of TCM then should provide a great resource for the search of new anticancer drugs [15], [16], [17].
Tetrandrine, which is consisted of about 1% in dried roots of Stephania tetrandra [18], has been reported with healing properties for allergy, angina pectoris, pulmonary fibrosis [19], and cancer [20], as well as calcium antagonism [21] and anti-viral activities [22]. These compelling biological activities have prompted many studies with the goal of drug development for the treatment of cancer. Tetrandrine also inhibits proliferation of tumor cells, increases the sensitivity of chemotherapeutic drugs and reverses multidrug resistance (MDR) of tumor cells [23], [24]. The effect on cell proliferation involves the regulation of the expression of cancer genes affecting mitochondria and endoplasmic reticulum, which in turn activating apoptosis pathway in cancer cells [25], [26]. The increased chemotherapeutic drug sensitivity and reversal of MDR in tumor cells is mainly mediated through inhibition of the expression of P-glycoprotein and reduces drug efflux [27], [28], [29].
Structurally, two benzyl tetrahydroisoquinoline are linked by ether linkages to form tetrandrine with tetrahydroisoquinoline N-methylation, bears an irregular eighteen-member ring. There are few reports about the structural modification of tetrandrine which mainly based on the introduction of halogens at the C5 and C14 positions, constructing C-C or C-N bonds by palladium catalyzed coupling reaction, preparing quaternary ammonium salts on the tertiary amine of isoquinoline [30], [31], [32], [33]. Recently, our group reported that amide-substituted tetrandrine derivatives exhibited good inhibitory activity against human hepatocellular carcinoma (HCC) [34]. Despite the huge potential of tetrandrine derivatives reported as an anticancer agent, it possesses several limitations for clinical application, including poor aqueous solubility and low bioavailability [35], [36].
Further study showed that inhibitors of protein kinases with fragments of aryl-urea, such as sorafenib, lenvatinib, tivozanib (Fig. 1), could effectively inhibit cells proliferation of human hepatocellular carcinoma, lung cancer, leukemia, prostate cancer, kidney cancer and other malignant neoplasms [37], [38], [39], [40]. In addition, urea moiety of some drugs could help to improve their pharmacological and pharmacokinetic profiles [41], [42]. In order to enrich the structural diversity of tetrandrine derivatives and obtain better anti-cancer drug cadidates, urea, aryl-urea as well as thiourea fragments were introduced into the structure of tetrandrine. We thus designed and synthesized a series of C14-urea-tetrandrine derivatives and studied their biological activities against tumor cells proliferation. The structure-activity relationship analysis (SARs) and mechanism of action of a compound with strongest anti-cancer activity were also studied in this report.
Section snippets
Chemistry
The synthetic routes of tetrandrine derivatives 3a-3x are shown in Scheme 1. Mild nitrification reagent was initially used at low temperature to selectively obtain C14 nitro-tetrandrine. Using hydrazine hydrate as a reduction agent in palladium carbon could readily convert the nitro derivative into an amino-substituted tetrandrine at a yield of 87% [34]. The C14-amino-tetrandrine was then reacted with isocyanate or carbamoyl chloride at room temperature in CH2Cl2 to give 24 novel C14
Conclusion
In conclusion, a series of novel C14-urea-tetrandrine derivatives was designed and synthesized. The evaluation of their inhibitory activities against HEL, K562, MDA-MB-231, PC3, WM9 cell lines showed that the anti-tumor activities of the C14-urea substituted derivatives were significantly higher than that of original compound tetrandrine. In general, derivative 4g showed the best anticancer activity on PC3 cells, which was 12 times more active than original compound tetrandrine, 31 times more
Methods of synthesis
Tetrandrine was purified from the roots of Stephania tetrandra by our group with purity ≥98%. Reagents and solvents were purchased from Adamas, JK chemical and local commercial sources. The reagents were used without futher purification unless otherwise noted and the solvents were purified according to the guidelines in Purification of Laboratory Chemicals. Column chromatography was performed on silica gel (Qingdao, 200–300 mesh) using the indicated eluents. Thin-layer (0.25 mm, GF254)
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No. 81360479 and 81472609), the Science and Technology Department of Guizhou Province (QKHRC [2016]4037, QKHSY [2015]3030).
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These authors contributed equally to this work.