The examination of shortened, simplified, and extended analogs of
duocarmycin SA is described and
constitutes a detailed study of the role of linked DNA binding subunit.
In addition to enhancing the DNA binding
affinity and selectivity through minor groove noncovalent contacts, the
studies in conjunction with those of the
accompanying article illustrate that an extended rigid N2
amide substituent is required for catalysis of the DNA
alkylation reaction. This activation for DNA alkylation is
independent of pH, and we propose it results from a
binding-induced conformational change in the agents which increases
their inherent reactivity. The ground state
destabilization of the substrate results from a twist in the linking
amide that disrupts the vinylogous amide stabilization
of the alkylation subunit and activates the agent for nucleophilic
addition. This leads to preferential activation of
the agents for DNA alkylation within the narrower, deeper AT-rich minor
groove sites where the inherent twist in
the linking amide and helical rise of the bound conformation is
greatest. Thus, shape-selective recognition
(preferential
AT-rich noncovalent binding) and shape-dependent catalysis (induced
twist in linking N2 amide) combine to restrict
SN2 alkylation to accessible adenine N3 nucleophilic sites
within the preferred binding sites. Additional
ramifications
of this DNA binding-induced conformational change on the reversibility
of the DNA alkylation reaction are discussed.
The results of the study illustrate the importance of the C5‘
methoxy group and the C6 methyl ester of duocarmycin
SA, and a previously unrecognized role for these substituents is
proposed.
A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.
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