Lima- Claudio G, Faheina-Martins Gláucia V, Bomfim Caio C B, Dantas Bruna B, Silva Everton P, Araújo Demetrius A M de, Filho Edilson B A, Vasconcellos Mário L A A
Laboratório de Síntese Orgânica Medicinal da Paraíba (LASOM-PB), Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil.
Med Chem. 2016;12(7):602-612. doi: 10.2174/1573406412666160506150924.
The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita-Baylis-Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-Leishmania chagasi and Leishmania amazonensis, anti- Trypanosoma cruzi, anti-Plasmodium falciparum and Plasmodium berghei, lethal against Biomphalaria glabrata, antibacterial, antifungal, herbicide and others.
The goal of this work is to describe the primary cytotoxic activities against strains of human leukemia HL-60 cell line for thirty-four Morita-Baylis- Hillman adducts (MBHA), followed by a Quantitative Structure-Activity Relationships study (QSAR).
The conventional or microwave-assisted syntheses of MBHA, derived from substituted aromatics or Isatin, were performed in good to excellent yields (70-100%) in short reaction times, using protocols recently developed by us. Isatin derivatives, MBHA 31 and 32, were the most active in this congener series of compounds, with IC50 values of 10.8 μM and 7.8 μM, respectively. The primary cytotoxic activities against chronic leukemia cells (K562) were also evaluated to these two most active compounds (MBHA 31 and 32), presenting IC50 values of 53 μM and 43 μM respectively. QSAR study was performed considering 3D, 2D and constitutional molecular descriptors. These were selected from Ordered Predictor Selection algorithm and submitted to Partial Least Squares Modeling.
We present an interesting investigation about cytotoxic activities on human leukemia cell line (HL-60) for 34 synthetic MBHA. In a good way we discovered that the most cytotoxic compounds (31-32, 10.8 μM and 7.8 μM respectively) were also prepared quantitatively (100% yields) in a short reaction time using microwave irradiation. We demonstrate that 31 and 32 induced apoptosis and not necrosis in HL-60 cells, observed by externalization of PS and increase Anexin-V positive cells. Quantitative Structure-Activity Relationships considering 3D, 2D and constitutional descriptors provided a robust and predictive PLS model, in accordance with SAR observations.
森田-贝利斯-希尔曼反应是一种有机催化的化学转化反应，可用于合成多官能小分子，具有巨大的合成潜力和良好的生物学特性。森田-贝利斯-希尔曼加合物（MBHA）是一类新型生物活性化合物，彰显了其在发现更廉价高效药物方面的潜力，例如对恰加斯利什曼原虫和亚马逊利什曼原虫、克氏锥虫、恶性疟原虫和伯氏疟原虫具有活性，对光滑双脐螺具有致死性，还具有抗菌、抗真菌、除草等活性。
本研究旨在描述34种森田-贝利斯-希尔曼加合物（MBHA）对人白血病HL-60细胞系各菌株的主要细胞毒性活性，并开展定量构效关系（QSAR）研究。
采用我们近期开发的方法，以取代芳烃或异吲哚酮为原料，通过常规或微波辅助合成法制备MBHA，反应时间短，产率良好至优异（70 - 100%）。在该类化合物中，异吲哚酮衍生物MBHA 31和32活性最高，IC50值分别为10.8 μM和7.8 μM。还评估了这两种活性最高的化合物（MBHA 31和32）对慢性白血病细胞（K562）的主要细胞毒性活性，IC50值分别为53 μM和43 μM。QSAR研究考虑三维、二维和结构分子描述符。这些描述符通过有序预测变量选择算法选出，并提交给偏最小二乘建模。
我们对34种合成的MBHA对人白血病细胞系（HL-60）的细胞毒性活性进行了有趣的研究。我们成功发现，细胞毒性最强的化合物（31 - 32，IC50值分别为10.8 μM和7.8 μM）在短反应时间内通过微波辐射定量制备（产率100%）。我们证明，31和32在HL-60细胞中诱导凋亡而非坏死，这通过磷脂酰丝氨酸外化和膜联蛋白-V阳性细胞增加得以观察到。考虑三维、二维和结构描述符的定量构效关系提供了一个稳健且具有预测性的偏最小二乘模型，与构效关系观察结果一致。
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