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Discovery of dolutegravir-1,2,3-triazole derivatives against prostate cancer via inducing DNA damage
Shuyi Zhou1, Xixi Hou2, Ling Li3
1Precision Research Center for Refractory Diseases in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
Prostate cancer (PCa) is the second most frequently diagnosed cancer among men, causing a huge number of deaths each year. Traditional chemotherapy for PCa mostly focused on targeting androgen receptors. However, some of the patients would develop resistance to hormonal therapy. In these cases, it is suggested for these patients to administer treatments in combination with other chemotherapeutics. Current chemotherapeutics for metastatic castration-resistant PCa could hardly reach satisfying effects, therefore it is crucial to explore novel agents with low cytotoxicity. Herein, a common drug against the human immunodeficiency virus (HIV), the dolutegravir (DTG) was modified to become a series of dolutegravir-1,2,3-triazole derivatives. Among these compounds, the 4d and 4q derivatives were verified with high anti-tumor efficiency, suppressing the proliferation of the prostate cancer cells PC3 and DU145. These compounds function by binding to the poly (adenosine diphosphate-ribose) polymerase (PARP), inactivating the PARP and inducing DNA damage in cancer cells. It is noteworthy that the 4d and 4q derivatives showed almost no impact on normal cells and mice. Thereby, the results reveal that these dolutegravir-1,2,3-triazole compounds are potential chemotherapeutics for PCa treatment.
Insights
Novel dolutegravir-1,2,3-triazole derivatives show potent anti-tumor effects against prostate cancer (PCa) by inhibiting PARP and inducing DNA damage. These compounds exhibit low cytotoxicity, offering a promising new therapeutic strategy for PCa treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Drug Discovery
Background:
- Prostate cancer (PCa) is a leading cause of cancer-related deaths in men.
- Hormonal therapy resistance is a significant challenge in advanced PCa treatment.
- Novel chemotherapeutics with low cytotoxicity are urgently needed for metastatic castration-resistant PCa.
Purpose of the Study:
- To develop novel dolutegravir-1,2,3-triazole derivatives as potential anti-cancer agents.
- To evaluate the anti-tumor efficacy of these derivatives against PCa cell lines.
- To investigate the mechanism of action of the most effective derivatives.
Main Methods:
- Synthesis of dolutegravir-1,2,3-triazole derivatives.
- In vitro evaluation of anti-proliferative activity against PC3 and DU145 PCa cell lines.
- Mechanism of action studies involving poly (adenosine diphosphate-ribose) polymerase (PARP) inhibition and DNA damage induction.
- Assessment of cytotoxicity in normal cells and mice.
Main Results:
- Dolutegravir derivatives 4d and 4q demonstrated significant anti-tumor efficiency by suppressing PCa cell proliferation.
- These compounds function by inhibiting PARP, leading to DNA damage in cancer cells.
- Derivatives 4d and 4q exhibited minimal impact on normal cells and mice, indicating a favorable safety profile.
Conclusions:
- Dolutegravir-1,2,3-triazole derivatives represent a promising new class of chemotherapeutics for prostate cancer.
- The PARP inhibitory activity and low cytotoxicity make these compounds attractive candidates for further clinical development.
- These findings offer a potential new treatment avenue for patients with advanced or treatment-resistant prostate cancer.
