Abstract
Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM). The naphtho[2,3-b]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3-b]furan-4,9-dione and naphtho[2,3-b]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r2 = 0.99 and q2 = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents.
Highlights
According to the World Health Organization (WHO), in 2012, 14 million cases and 8.2 million deaths were attributed to cancer, a disease characterized by abnormal and uncontrolled growth of Molecules 2018, 23, 186; doi:10.3390/molecules23010186 www.mdpi.com/journal/moleculesMolecules 2018, 23, 186 cells and colonization of tissues; which is documented as the second cause of mortality after cardiovascular diseases, and is expected to surpass 20 million new cases by 2025 [1].The colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, after lung and breast cancer, and constitutes the fourth cause of cancer death [2]
The results are expressed as the mean of triplicate measurements in at least two independent experiments
We synthesized a series of naphthoquinone derivatives and evaluated their anti
Summary
According to the World Health Organization (WHO), in 2012, 14 million cases and 8.2 million deaths were attributed to cancer, a disease characterized by abnormal and uncontrolled growth of Molecules 2018, 23, 186; doi:10.3390/molecules23010186 www.mdpi.com/journal/moleculesMolecules 2018, 23, 186 cells (tumor) and colonization of tissues (metastasis); which is documented as the second cause of mortality after cardiovascular diseases, and is expected to surpass 20 million new cases by 2025 [1].The colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, after lung and breast cancer, and constitutes the fourth cause of cancer death [2]. Molecules 2018, 23, 186 cells (tumor) and colonization of tissues (metastasis); which is documented as the second cause of mortality after cardiovascular diseases, and is expected to surpass 20 million new cases by 2025 [1]. Current treatment of CRC employs surgical resection combined with chemotherapy, cytotoxic drugs, and radiotherapy [6]. These therapies are often ineffective, mainly due to the resistance developed by cancer stem cells, leading to recurrence in a significant amount of patients with late-stage
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