THEORETICAL AND QSAR STUDIES OF ANTHRACYCLINES AND THEIR ANALOGS

蒽环类药物及其类似物的理论和 QSAR 研究

• 批准号: 6240337
• 负责人: YITBAREK H MARIAM
• 金额: $ 11.79万
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240337
• 关键词: analog; anthracyclines; antineoplastic antibiotics; chemical models; chemical reaction; chemical structure function; conformation; daunorubicin; doxorubicin; drug design /synthesis /production; drug interactions; electron spin resonance spectroscopy; electronic spectra; free radicals; mass spectrometry; mathematical model; nuclear magnetic resonance spectroscopy; quantum chemistry; tautomer

Theoretical studies of the reactivity of model systems for the pharmacophores of the anthracycline family of drugs will be undertaken using semiempirical formalisms. (AM1, AM1-SM1/SM2, ETC). The thrust of these studies is to gain insight from quantum chemistry/pharmacology, molecular modeling and statistical inference to understand molecular- level features that govern chemical reactivity but are concealed by the molecular structure and raw experimental data. Electronic properties (absolute electronegativity and hardness; HOMO, LUMO and SOMO orbital energies; enthalpy of reaction for electron attachment; free energies of solvation, etc.) of some 16 and 42 derivatives of naphthaquinone and anthraquinone, respectively, will be calculated and used as variables for the purpose of correlating the variables with experimental one- and two- electron reduction potentials. The electronic properties will also be correlated with antitumor activity (ED25) and acute toxicity (LD50) for those cases where such data are available. Simulated annealing techniques will be used to study the relative stabilities of conformers/rotamers, keto-enol forms and radicals. Solvation free energies will be calculated to determine their (or, in combination with other electronic properties) possible correlations with reduction potentials, antitumor activity (ED25) and acute toxicity (LD50). The studies will be used to develop structure/activity relationships which will, in turn, be used to predict the biological activities of theoretical models - not yet-synthesized-drugs.

模型系统反应性的理论研究 将进行蒽环类药物家族的药算团 使用半经验形式主义。 （AM1，AM1-SM1/SM2等）。 推力 这些研究是为了从量子化学/药理学中获得见解， 分子建模和统计推断以了解分子 控制化学反应性但被隐藏的水平特征 分子结构和原始实验数据。 电子特性 （绝对的电负性和硬度； HOMO，LUMO和SOMO ORBITAR 能量；电子附着的反应焓；自由的能量 溶剂化等）大约16和42个萘醌的衍生物 分别将计算并将其用作变量 将变量与实验的一单和二 - 相关的目的 电子还原电位。 电子特性也将是 与抗肿瘤活性（ED25）和急性毒性（LD50）相关 那些可用的数据的情况。 模拟退火 技术将用于研究 构象体/旋转剂，酮 - 烯醇形式和自由基。 无溶剂 将计算能量以确定其（或与 其他电子特性）可能与减少的相关性 电势，抗肿瘤活性（ED25）和急性毒性（LD50）。 这 研究将用于建立结构/活动关系 反过来，将被用来预测 理论模型 - 不是合成的药物。