四环素类抗生素药物的发现、发展与合成:源于天然产物,用于人类健康

Discovery,development and syntheses of tetracycline antibiotics:derivation from natural products and application for human health

四环素类抗生素是一类广谱抗生素,广泛应用于治疗由革兰阳性和阴性细菌、支原体、衣原体和立克次氏体感染所引起的疾病.四环素类抗生素药物由ABCD四个六元并环骨架结构所构成.目前,人们主要通过发酵途径获得四环素类天然抗生素,再通过化学半合成的方式对其进行结构改造,其中A环取代方式固定,人们主要对D环作结构改造以获得临床药效更加优异的非天然新型四环素类抗生素药物.自1962年四环素Sancycline全合成工作以来,合成工作者们完成了多个四环素类抗生素药物的全合成,如近年通过发展新颖合成策略完成了四环素类抗生素药物Doxycycline的全合成;其后,人们通过全合成高效地完成了其他四环素类抗生素药物的合成和结构改造,加速了新型四环素类抗生素药物的研发与上市.本综述归纳总结了四环素类药物的发现和发展史,并介绍了其生物合成机制和针对病原菌的药物作用模式,详细介绍并比较了各种四环素类药物的半合成和全合成方式,将为研究者了解四环素抗生素及其结构类似药物的发现、发展和合成空间等起到有益作用.

Tetracycline antibiotics,a class of broad-spectrum antibiotics,are widely used in the treatment of diseases caused by gram-positive and gram-negative bacteria,mycoplasma,chlamydia and rickettsia infections.Tetracycline antibiotics consist of four fused six-membered cycles,i.e.,ABCD tetracyclic system.To date,people mainly obtain tetracycline natural antibiotics through fermentation,and then carry out structural modification through chemical semisynthesis.Among them,the substitution in ring A is found invariable while the modification in ring D is worth exploring so as to obtain new non-natural tetracycline antibiotic drugs with better clinical efficacy.Since the completion of the total synthesis of tetracycline in 1962,synthetic communities have accomplished several tetracycline antibiotic drugs,such as recent total synthesis of tetracycline antibiotic drug Doxycycline via novel synthetic strategies;then the total synthesis and structural modifications of other tetracycline antibiotics were efficiently fulfilled which accelerated the development and marketing of new tetracycline antibiotics.In this review,the discovery and developing history of tetracycline drugs is summarized,and their biosynthetic mechanism and drug action mode against pathogenic bacteria is described,besides the semi-synthetic and total synthesis of various tetracycline drugs,which will play an instructive role for researchers to understand the discovery,development and synthetic scope of tetracycline antibiotics and structurally similar drugs.