Molecular orbital calculations, experimental and theoretical UV spectra of granulatimides and didemnimides, biologically active polycyclic heteroaromatic alkaloids from the ascidian Didemnum granulatum

A detailed computational study was performed for compounds granulatimide, isogranulatimide. and didemnimides A, D, and E, using the semiempirical Austin model 1 quantum chemical method. The electronic features and structural parameters were confronted with the inhibition of the G2 cell cycle checkpoint of mammalian cancer cells. All compounds were submitted to a rigorous conformational analysis using the Tripes 5.2 force field implemented in the Spartan 5.01 program. The electronic density in specific regions of the molecules appears to play a pivotal role towards activity. The molecular planarity creates a broad negative electrostatic potential on the two sides of the active compounds (granulatimide and isogralulatimide) and a positive potential in their central core, while the non-planar compounds (didemnimides A, D, and E, which are inactive) present an asymmetric potential scattered over the molecules. These electrostatic potential features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds, which appear correlated with activity. The hydrogen attached to the N atom of the pyrrole moiety of indole is more positive for active compounds than for the inactive molecules. The theoretical electronic spectra were obtained for all compounds using the configuration interaction method, with the AM1 routine. All transitions present pi --> pi* nature. The theoretical results are in good agreement with experimental values. (C) 2001 Elsevier Science B.V. All rights reserved.