Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase
Madhuri Dasari1, Stephen C Pelly1, Jiafeng Geng1
1Department of Chemistry, Emory University College of Arts and Sciences, Atlanta, Georgia 30322, United States.
Abstract:
5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic events that can drive undesired systemic toxicity. Our previous research on antiviral nucleotides suggested that substitution at the nucleoside 5'-carbon imposes conformational restrictions on the corresponding nucleoside monophosphates, rendering them poor substrates for productive intracellular conversion to viral polymerase-inhibiting triphosphate metabolites. Accordingly, we hypothesized that 5'-substituted analogs of FdUMP, which is uniquely active at the monophosphate stage, would inhibit TS while preventing undesirable metabolism. Free energy perturbation-derived relative binding energy calculations suggested that 5'(R)-CH3 and 5'(S)-CF3 FdUMP analogs would maintain TS potency. Herein, we report our computational design strategy, synthesis of 5'-substituted FdUMP analogs, and pharmacological assessment of TS inhibitory activity.
Insights
New 5'-substituted analogs of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) show promise for cancer treatment. These compounds inhibit thymidylate synthase (TS) while potentially reducing systemic toxicity associated with traditional 5-fluorouracil therapies.
Area of Science:
- Medicinal Chemistry
- Cancer Pharmacology
- Drug Design
Background:
- 5-Fluorouracil (5-FU) and its prodrugs are established cancer therapeutics.
- Their primary mechanism involves thymidylate synthase (TS) inhibition by 5-fluoro-2 '-deoxyuridine 5 '-monophosphate (FdUMP).
- Current 5-FU therapies suffer from dose-limiting systemic toxicities due to unfavorable metabolism.
Purpose of the Study:
- To design and synthesize novel 5 '-substituted FdUMP analogs.
- To hypothesize that these analogs would inhibit TS while preventing detrimental metabolic conversion.
- To explore a strategy for improved cancer treatment with reduced side effects.
Main Methods:
- Computational design utilizing free energy perturbation calculations.
- Synthesis of novel 5 '-substituted FdUMP analogs.
- Pharmacological assessment of thymidylate synthase (TS) inhibitory activity.
Main Results:
- Computational analysis predicted that 5 '-(R)-CH3 and 5 '-(S)-CF3 FdUMP analogs would retain TS inhibitory potency.
- Synthesis of these novel 5 '-substituted FdUMP analogs was successfully achieved.
- Initial pharmacological assessments of TS inhibitory activity were conducted.
Conclusions:
- 5 '-substituted FdUMP analogs represent a promising new class of TS inhibitors.
- This approach may lead to more effective cancer chemotherapeutics with improved safety profiles.
- Further investigation into the therapeutic potential of these analogs is warranted.
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