Design and Synthesis of 8-Amino Pyrrolo[2,1-c][1,4 ]benzodiazepine Hybrid Agents

• Main Authors: Ke, Dei-She, 柯迪旭
• Other Authors: Jeh-Jeng Wang
• Format: Others
• Language: zh-TW
• Published: 1997
• Online Access: http://ndltd.ncl.edu.tw/handle/33625923895488295251

碩士 === 高雄醫學院 === 天然藥物研究所 === 85 === Since the earlier naturally-occurring pyrrolo[2,1-c][1,4 ]benzodiazepine ( PBD ) "anthramycin", which was produced by the Streptomyces NRRL 3143, waspurified and characterized, lots of natural PBDs were found and studied. Thecarbinolamine-containing PBDs family of antitumor antibiotics are produced byvarious Streptomyces species. Well-known members include tomaymycin, prothra- carcin and sibiromycin. The antitumor activity of the PBDs is exerted throughsequence-selective covalent binding to N-2 of guanine within the minor grooveof double-stranded DNA via the electrophilic N10-C11 carbinolamine-imine functionality. The covalent binding of PBD-DNA adducts are irreversible. Thusthe resulting adducts lead to a number of biological effects including inhibition of DNA replication. The NH group of indoles could bind to N-3 of adenine and O-2 of thymine by forming hydrogen bonds. To increase the sequence-selectivity, we present the design and synthesis of hybrid agents based uponthe PBD and indole moieties. The pyrrolidine-2-carbaldehyde diethyl dithioacetal was coupled to 2,4- dinitrobenzoyl chloride at room temperature and basic condition, to afford (2S)-N-(2,4- dinitrobenzoyl)pyrrolidine-2-carbaldehyde diethyl thioacetal. Reductionof the nitro groups with stannous chloride afforded the amino groups. Indole-2-carboxylic acid was coupled to 4-amino group of the aromatic ring with EDCI, then the compound was cyclised ( HgCl2 / CaCO3 ) to afford (11aS)-8-(1H-2-indo- lylcarboxamido)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4 ]benzodiazepine-5-one.