在这项工作中,我们从天然细胞毒性查尔酮2'进行了新的嵌合化合物的设计和合成,4\'-二羟基查耳酮(2\',4\'-DHC,A)与肉桂酸结合使用。为此,建立了描述性和预测性定量结构-活性关系(QSAR)模型,以研究嵌合化合物对人乳腺癌MCF-7的抗癌活性,依赖于查尔酮结构中是否存在结构基序,就像在自由威尔逊的方法。为此,我们使用了207个在α和β环上具有多种结构修饰的查尔酮衍生物,如卤素(F,Cl,andBr),杂环(哌嗪,哌啶,吡啶,等。),以及羟基和甲氧基。通过遗传算法技术获得了多元线性方程,使用logIC50作为因变量和分子描述符(宪法,拓扑,功能组计数,以原子为中心的碎片,和分子性质)作为独立变量,具有可接受的统计参数值(R2=86.93,Q2LMO=82.578,Q2BOOT=80.436,Q2EXT=80.226),支持模型的预测能力。考虑到查尔酮和肉桂酸核的芳香和平面性质,通过将几何描述符结合到以前的通用QSAR模型中,开发了结构特定的QSAR模型,再次,参数可接受(R2=85.554,Q2LMO=80.534,Q2BOOT=78.186,Q2EXT=79.41)。将这种新的QSAR模型应用于天然母体查尔锥2',4'-DHC(A)和嵌合化合物2'-羟基,4\'-肉桂酸查尔酮(B),预测的细胞毒性活性分别为55.95和17.86µM,分别。因此,为了证实预测的细胞毒性活性,通过两步和三步反应合成化合物A和B。通过1H和13CNMR和ESIMS分析确认了结构,并在体外对HepG2,Hep3B(肝)进行了进一步评估,A-549(肺),MCF-7(乳房),和CasKi(宫颈)人类癌细胞系。结果显示IC50值为11.89、10.27、56.75、14.86和29.72µM,分别,对于嵌合肉桂酸查尔酮B,最后,我们使用B作为分子支架来产生肉桂酸候选物(C-K),其中掺入了增强细胞毒性活性的结构基序(吡啶环,卤素,和甲氧基)根据我们的QSAR模型。ADME/tox的模拟分析表明,合成的化合物A和B,以及拟议的查耳酮C和G,是具有足够药物相似性的最佳候选人。从所有这些结果来看,我们提出B(作为分子支架)和我们的两个QSAR模型作为在MCF-7细胞系上产生抗癌化合物的可靠工具。
In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2\',4\'-dihydroxychalcone (2\',4\'-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds\' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2\',4\'-DHC (A) and the chimeric compound 2\'-hydroxy,4\'-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C-K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.