Pichierri Fabio, Galasso Vinicio
COE Laboratory, Tohoku University, IMRAM, 2-1-1 Katahira, Sendai 980-8577, Japan.
J Phys Chem A. 2007 Jul 5;111(26):5898-906. doi: 10.1021/jp071851x. Epub 2007 Jun 12.
Molecular structure and conformational preferences of yatakemycin, a novel and exceptionally potent antitumor agent, have been investigated using the density functional theory (DFT) formalism. From the relative stability of various possible conformations, it is found that two conformers are nearly isoenergetic and markedly more stable than the others in the gas phase. To test the effect of polar mediums, the relative energies have been recalculated using the self-consistent reaction field method. Thus, the most stable conformer of the isolated molecule in the gas phase is expected to be still more preferred in solution. The molecular structure of yatakemycin has also been studied by means of its spectroscopic properties. The DFT results satisfactorily reproduce the experimental data and corroborate the reliability of the structural characterization advanced for yatakemycin. The lowest-energy electronic transitions have been interpreted with time-dependent DFT calculations. Notably, the strong IR band observed at 2852 cm(-1) is unambiguously assigned to the O-H stretching of the (C7)O-H...O(C12) fragment, linked by a strong intramolecular H-bond, and may be viewed as a distinctive fingerprint of yatakemycin. Furthermore, the calculated set of NMR chemical shifts of carbonyl carbon atoms and indole protons, the most sensitive to stereoelectronic factors, is consistent with experiment. The effects of both protonation and oxidation on the geometry of the most stable conformer have also been studied. With reference to yatakemycin's DNA alkylation properties, the structure of the yatakemycin-adenine adduct has been theoretically modeled and found to be consistent with experimental spectroscopic evidence.
利用密度泛函理论（DFT）方法研究了新型高效抗肿瘤药物 yatakemycin 的分子结构和构象偏好。从各种可能构象的相对稳定性来看，发现有两种构象在气相中能量几乎相等，且明显比其他构象更稳定。为了测试极性介质的影响，使用自洽反应场方法重新计算了相对能量。因此，预计气相中孤立分子最稳定的构象在溶液中仍更受青睐。还通过其光谱性质研究了 yatakemycin 的分子结构。DFT 结果令人满意地重现了实验数据，并证实了对 yatakemycin 提出的结构表征的可靠性。利用含时 DFT 计算解释了最低能量的电子跃迁。值得注意的是，在 2852 cm(-1) 处观察到的强红外带明确归属于通过强分子内氢键相连的 (C7)O-H...O(C12) 片段的 O-H 伸缩振动，可视为 yatakemycin 的独特指纹。此外，对羰基碳原子和吲哚质子最敏感的立体电子因素的一组计算 NMR 化学位移与实验结果一致。还研究了质子化和氧化对最稳定构象几何结构的影响。参照 yatakemycin 的 DNA 烷基化性质，对 yatakemycin - 腺嘌呤加合物的结构进行了理论建模，发现与实验光谱证据一致。
