Design,Synthesis And Activity Evaluation Of Novel Teniposide Derivatives

As a representative class of anti-tumor glycoside compounds,"teniposide"was designated as an anti-cancer first-line drug by the FDA?Food and Drug Administration?in the 1980s and has been widely used in testicular cancer,lymphoma,leukemia,non-small cell lung cancer,acute Human leukemia and other multiple cancer treatments.However,teniposide has room for further improvement in pharmacology such as increased activity and high side effects.It is necessary to discover new teniposide analogue with prospects for drug use through molecular structure modification.In this work,as a functional module,fluorobenzothiazole or oxazole derivatives,which can enhance antitumor activity and reduce toxicity,are summarized in the previous study,and fluorine-containing benzothiazoles or oxazoles are introduced into teniposide via ester bonds or amide bonds.The 2'',3''position of glycosyl was designed as a series of4'-demethylepipodophyllotoxin-4?-D-thiophenemethylene-2'',3''-Benzoheterocycles substituents for glucopyranoside derivatives.Selected azide as the“amino protecting group”,classical acetyl protecting reaction,bromination reaction and S_N2 reaction,etc.,glycosyl donor was established,direct condensation approach for glycosidic bond,an efficient 7 steps approach for intermediates?2''-amino-teniposide?was established.Designed and synthesized a series of teniposide glycosyl 2"or 3"fluorobenzothiazole or oxazole derivatives modified by ester or amide linkages.The four tumor cell lines Hep G2,lung cancer A549,breast cancer MCF-7,cervical cancer HeLa and the corresponding four normal cell hepatocytes HL-7702,lung cell MRC-5,mammary cell HMEC,cervical cell H8 were tested The cells were tested for cytotoxicity.The toxicity evaluation results showed that the activity of compounds 1⁴was better than the marketed podophyllotoxin drug Etoposide,compound 9 and compound 10 against tumor cell activity equivalent to that of etoposide,The IC₅₀ of compound 9 and compound 10 against normal cell HL-7702 were all higher than 100?M.The toxicity were lower than the positive reference"Etoposide"(IC₅₀=24.75?M).At the same time,compounds 1⁴ against HepG2,A549,MCF-7 and HeLa,caused obvious G2/M phase arrest at 18 hours,and 40%of G2/M cycle arrest at 42 hours.70%⁹8%higher than"Etoposide"?30%⁷0%?.The apoptotic rate of HepG2,A549,MCF-7 and HeLa induced by 1⁴ were higher than 60%,which were higher than that of etoposide?20%⁴0%?.Compound 9 and compound 10 against HL-7702 for 42 h,and the cycle resist of G₂/M phase were less than 30%,lower than that of etoposide?70%?.When compound 9 and compound 10 were treated to HL-7702 for 42 h,the apoptosis rate were lower than 35%,indicated that the toxicity of compound 9 and compound 10were lower than that of etoposide.In this work,Ten of 4'-demethylepipodophyllotoxin-4?-D-thiophenemethylene-2''/3''-benzoheterocyclic substituted glucopyranoside derivatives were designed and synthesized.A synthetic route for the 7 steps 2"-amino-teniposide derivative was established,which is expected to simplify the synthetic route of NK-611 in clinical phase II and shorten the original 13 steps synthetic route.Compound 9 and compound10 with significantly reduced toxicity were screened,and the analysis of the structure-activity relationship showed that mono-esterification was beneficial to increase activity,and mono-amidation modification was beneficial to reduce toxicity,laid the foundation for drug modification directions.