Dictyostatin Flexibility Bridges Conformations in Solution and in the β-Tubulin Taxane Binding Site

Abstract

Dictyostatin (DCT, 1) is a complex, flexible polyketide macrolide that demonstrates potent microtubule-polymerization activity. Both a solution structure (2a) and a possible binding mode for DCT (Conf-1) have been proposed by earlier NMR experiments. In the present study, the conformational landscape of DCT in DMSO-d(6) and methanol-d(4) was explored using extensive force-field-based conformational searches combined with geometric parameters derived from solution NMR data. The results portray a diversity of conformations for dictyostatin that illustrates the molecule's flexibility and excludes the previously suggested dominant solution conformation 2a. One conformation present in DMSO-d(6) with a 7% population (Conf-2, 0.6 kcal/mol above the global minimum at 298°) also satisfies the TR-NOESY NMR parameters of Canales et al. that characterize the taxane binding-site interaction between DCT and assembled microtubules in water. Application of several docking methods (Glide, Autodock, and RosettaLigand) has identified a low-energy binding model of the DCT/β-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data.

Conformational analysis: 3JHCOC and 3JHCCC Karplus relationships for methylene 1H nuclei

“…Even with this wide selection (1185 + 1), in which we could potentially find a completely different conformational mixture for each of the two sets, it is pleasing to note that there is a significant degree of cross‐over (33–40%), in the selection of conformers 220 and 711. The X‐ray conformation is not selected despite reports of other NAMFIS studies indicating the presence of the solid‐state structure amongst the solution conformations …”

“…Consideration has been given to the HCOC and HCCC bond angles for pathways 25/26‐11‐10‐2 and 25/26‐11‐12‐13, and the resultant average 3 J CCs that arise from the conformation of A2OB as determined by X‐ray diffraction, based on the proposal that this conformation may be present in solution, although this is not always the case . There is an excellent match for the crystal structure in the conformer pool, conformer 821 (Fig.…”

Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

“…These studies, founded on total synthesis, were largely complementary and together provide a solid if still evolving [24] picture of dictyostatin SAR. Phillips [25], Ramachandran [26] and Gennari [27] have also developed efficient synthetic routes to the natural product or fully functionalized analogs.…”

A Highly Step‐Economical Synthesis of Dictyostatin

“…[6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports. In addition, the Paterson/Wright [16] and Curran/Day [17] teams have reported extensive SAR studies, while the Paterson/Díaz/Jiménez-Barbero [18] and Curran/Snyder [19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on β-tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis.…”