| Abstract: |
Menogaril (7-con-O-methylnogarol) is a derivative of the anthracycline antitumor drug nogalamycin lacking both the nogalose sugar and acetyl functionality that are positioned in the minor groove of the nogalamycin-DNA complex. Two menogaril molecules bind to the self-complementary d(G1-A2-C3-A4-T5-G6-T7-C8) duplex in a cooperative manner and form a symmetric two drugs per duplex complex. We have obtained the solution structure of the menogaril-d(G-A-C-A-T-G-T-C) complex by a combined NMR-molecular dynamics study including intensity-based refinement. The aglycon chromophore of menogaril intercalates between (C3-A4)•(T5-G6) base pairs, with its long axis orthogonal to the long axis of the flanking Watson-Crick base pairs. The B, C, and D aromatic rings of the aglycon chromophore stack primarily with the G6 base with the OH-4/OH-6 bearing edge directed toward the C3-A4 strand, while the nonplanar cyclohexene ring A protrudes into the minor groove and adopts a half-chair conformation. An intermolecular hydrogen bond is detected between the OH-9 of the cyclohexene ring A and O2P of the G6-T7 step in the minor groove. The positively charged bicyclic aminoglucose sugar which is fused to the aromatic ring D of the aglycon is positioned in the major groove and spans the three base pair d(A2-C3-A4)•d(T5-G6-T7) segment. The aminoglucose sugar adopts a chair conformation with the bridgehead oxygen atom directed toward the A4•T5 base pair and the charged N(CH3)2-3′′ group directed toward the A2-T7 base pair. A strong intermolecular hydrogen bond is detected between the OH-2′′ of the bicyclic aminoglucose sugar and the N7 of G6 in the major groove, which accounts for the sequence specificity of menogaril for its target sites on DNA. Intercalation of the aglycon of menogaril through the major groove contrasts with the majority of antitumor antibiotics which intercalate into DNA through the minor groove. © 1995, American Chemical Society. All rights reserved. |
