Base-Modified Nucleosides as Chemotherapeutic Agents: Past and Future

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Pharmacology

Background:

• Nucleoside and nucleobase antimetabolites are crucial in treating cancer and infections.
• Their efficacy stems from mimicking natural analogs to disrupt cellular targets.
• However, this mechanism leads to significant side effects, particularly with chemotherapeutics for malignancies.

Purpose of the Study:

• To review current antimetabolite drugs and emerging nucleoside drug candidates.
• To explore nucleobase modification strategies for novel analogs.
• To focus on developing analogs that terminate DNA synthesis, potentially reducing toxicity in non-proliferating cells.

Main Methods:

• Literature review of existing antimetabolite drugs (e.g., 5-fluorouracil, cladribine).
• Analysis of ongoing research into new nucleoside drug candidates.
• Discussion of synthetic approaches for nucleobase modifications.

Main Results:

• Identified key current antimetabolite drugs and their applications.
• Highlighted promising nucleoside drug candidates in development.
• Outlined strategies for modifying nucleobases to enhance therapeutic windows.

Conclusions:

• Novel nucleoside analogs with improved therapeutic windows are highly desirable.
• Targeting DNA synthesis termination may offer a strategy to reduce off-target toxicity.
• Continued research in synthetic organic and medicinal chemistry is essential for discovering safer, more effective antimetabolites.