| Summary: | 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.
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