Design, Synthesis Of Novel Larotaxel And Baicalein Analogues And Their Bioactivities Against Multidrug-resistant Cancer Cells

Cancer is a class of diseases which endanger human life and quality of life. For several decades, many high cytotoxic agents have been applied to the first-line treatments for a wide variety of cancers in cancer chemotherapy. However, multidrug resistance (MDR) limited the success of therapy in patients treated long-term with chemotherapeutic drugs. The drug resistance is mainly due to the overexpression of the P-glycoprotein (Pgp) which is known to cause subtherapeutic intracellular drug concentrations. For example, although the famous paclitaxel (Taxol) and docetaxel (Taxotere) possessed highly potent antitumor activity, it exhibited low or no cytotoxicities against some drug-resistant (P-gp+) cells due to it acted as a good substrate of P-gp protein. Therefore, the research and development trend of paclitaxel is to develop new taxane anticancer agents with improved activity against various classes of tumors, especially against drug-resistant human cancer.Traditional Chinese medicines have been recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to reduce the side effects of cancer chemotherapies. Baicalein, as a bioactive flavonoid, is one of the most popular used to treat many diseases in China and in several oriental countries. Its anti-tumor effects were weaker than other high cytotoxic agents, but it acted as a good inhibitor of P-gp and showed low toxicity toward normal tissues. Therefore, much investigations have been focused on researching and developing baicalein derivatives with better anti-tumor activities. Study on the Efficient and Large-scale Preparation of LarotaxelLarotaxel (XRP-9881) is a novel taxane derivative with preclinical activity against taxane-resistant breast cancer and has been finished in phaseⅢnow. In addition, it can also penetrate the blood brain barrier (BBB) which may also be a consequence of its decreased recognition by the P-gp.In this paper, we have developed an efficient and practical method for the large-scale preparation of larotaxel from deacetylbaccatinⅢand other cheap and readily starting materials. We improved and applied the racemic "β-Lactam Synthon Method" to the large scaled synthesis of the C-13 side chain of larotaxel. It was found that the size of the silyl protecting groups at the 3-hydroxy moiety ofβ-lactams had an important influence on the diastereoselectivity of the resolution. The tert-butyldimethylsilyl protecting group provided optimum kinetic resolution in comparison with the the larger tri-isopropylsilyl and tert-butyldiphenylsilyl group in the reactions investigated. The synthesis technology contains a total of 11-step reaction, and 8-step reaction without further purification among them, which greatly reduced the production cycle. The new synthetic method was verified by amplifying and was indicated that the process is low-cost, high-yield and controllable and so on. Study on the Design and Synthesis of Novel Anti-MDR-tumour Taxoid AnaloguesIn this paper, 23 new generation taxoids with systematic and strategic modifications at the C2, C10, and C3′positions of larotaxel were designed, synthesized, and examined for their inhibitory activities against the growth of a human oral squamous epithelium cancer cell line KB, a human breast cancer cell line MCF-7 and their P-gp 170 protein overexpressing cell lines KB/VCR, MCF-7/ADR. Their preliminary structure-activity relationships have been concluded. As a result, many of these taxoids exhibited exhibited relatively low resistance factors than larotaxel (XRP9881) and cabazitaxel (XRP6258). Many fluorinecontaining taxoids were also designed and investigated. Among them, 3′-difluorovinyl-taxoids were found to exhibit exceptionally high potency against multidrug-resistant cancer cell lines. Compounds LTX-104、LTX-106、LTX-118 exhibited much higher activity than larotaxel and cabazitaxel against multidrug-resistant cancer cell lines KB/VCR and MCF-7/ADR. They also respectively possess about two to four orders of magnitude higher potency than paclitaxel and docetaxel against drug-resistant cancer cell line MCF-7/ADR.Study on the Design and Synthesis of A-ring Modified Anti-tumour Baicalein DerivativesA series of baicalein derivatives modified on the A–ring were synthesized and screened for their inhibitory activities against the growth of KB、MCF-7 and their P-gp 170 protein overexpressing cell lines KB/VCR, MCF-7/ADR. The results indicated that modifications on 5-hydroxyl group may be not very important for their anticancer activities. Acylations of 6-hydroxyl group exhibited similar or better activities against both drug-sensitive and drug-resistant cell lines, which depended on the substitutions of 7-hydroxyl group. However, alkylations of 6-hydroxyl group generally resulted in reduced or completely loss of activities. The appropriate alkylations of 7-hydroxyl position may be favorable for the bioactivities. Among them, compounds HQS-5、HQS-17、HQS-24 exhibited higher inhibitory activities than baicalein against all the four cell lines, especially against drug-resistant cancer cells. Furthermore, the growth inhibitory IC50 of the active compounds against both drug-sensitive and drug-sensitive cancer cells are about the same, indicating that these compounds are unlikely to be the substrates of P-gp 170 protein. The preliminary SAR of baicalein on the A–ring will be favor in designing better baicalein derivatives acted as a chemotherapy adjuvant to enhance the efficacy of cancer therapeutics.