Researches On Anti-MDR Anticancer Drugs

Cancer has been one of the biggest killers for human being and threatens the health of the entire world. The development of new anticancer drugs has all along been the major tasks for the medicinal chemists and organic chemists. The multidrug resistance of human malignancy to multiple chemotherapeutic agents remains a major obstacle in cancer therapy. In the recent year, the development of anti-MDR anticancer drugs has become a major focus of research. The details and results are summarized below:(1) Sugars were acetylated with acetic anhydride and anhydrous sodium acetate to give the corresponding acetylated sugars. The anomeric O-acetyl group of acetylated sugars was selectively removed with hydrazine acetate or with NaOCH3 to afford 1-OH acetylated sugars. The 1-OH of these compounds was activated by trichloroacetonitrile with presence of potassium carbonate yielded acetyl-α-glycosyl tirchloroacetimates. Aforesaid compounds as glycosyl donors reacted with shikonin under BF3·EtO2 and 4 A molecular sieve at nitrogen atmosphere to furnish the corresponding shikonin acetyl-β-glycosides, and 11 new compounds were provided. Shikonin reacted with isocyanates in toluene to afford 1'-shikonin carbamates, and 12 new compounds were provided. Shikonin acetyl1-β-glycsides and 1'-shikonin carbamates were evaluated for their antitumor and anti-MRD activity in vitro.(2) Wang resin condensated with Fmoc-glycine, and Fmoc group was removed in presence of piperidine, and it was esterified with propionic acid under EDCI to afford the prop-gly-wang resin. Using toluenesulfonic acid as catalyst glucose reacted with acetone to form diisopropylidene glucofuranose.3-OH of this compound was esterified by Tf2O to afford diisopropylidene-3-O-Tf-glucofuranose, which reacted with NaN3 to form diisopropylidene-3-azido-allofuranose. Aforesaid compound was removed diisopropylidene group under HCl in MeOH to provide 3-azido-allopyranose. 3-Azido allopyranose was esterified by acetic anhydride and deprotected 1-actyl group using hydrazine acetate as catalyst to afford triacetyl-3-azido allopyranose. The compound reacted with trichloroacetonitrile to form triacetyl-3-azido allosyl trichloroacetimidate. Catalyzed by BF3. Et2O and 4 A molecular sieves, aforesaid compound reacted with shikonin to provide shikonin 3-azido triacetyl alloside, which linked with prop-gly-wang resin to provided shikonin wang resin under click reaction condition. Using sepharose 6B as a support, it was efficiently linked with shikonin in a new reactor to afford sh-sepharose 6B. Shikonin wang resin and sh-sepharose 6B were used for identifying shikonin-binding protein.(3) An cascade reaction of hydrazones, azodicarboxylates and triphen-ylphosphines has been developed. When 2 equiv of azodicarboxylates was used,4-alkyl(carbalkoxy)amino-triazolinones was obtained. This novel and general method provided 18-member library of 4-alkyl (carbalkoxy)-amino-triazolinones with yields of 58-98%. These compounds were evaluated for their antitumor and anti-MRD activity in vitro. We proposed a plausible mechanism for this approach.(4) An ABC style cascade reaction of aldehyde, hydrazine and azodicarboxylates to 4-(carbalkoxy)amino-triazolinones has been developed. This simple and efficient one-pot synthesis yielded 22-member library of 4-(carbalkoxy)amino-triazolinones with yields 59-98%, which were examined for their antitumor and anti-MRD activity in vitro. A plausible mechanism has been proposed.