NAD-analogues as potential anticancer agents: conformational restrictions as basis for selectivity

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• Inosine monophosphate dehydrogenase (IMPDH) is a crucial enzyme in de novo purine biosynthesis.
• IMPDH is a validated target for anticancer therapies due to its overexpression in neoplastic cells.
• NAD-analogues represent a promising class of IMPDH inhibitors.

Purpose of the Study:

• To synthesize and evaluate novel cofactor-type inhibitors of IMPDH.
• To explore the potential of these analogues as anticancer agents.
• To investigate the structure-activity relationships of NAD-analogues with modified nucleoside moieties.

Main Methods:

• Synthesis of C-nucleoside isosteres of NAD (C-NAD, C-PAD).
• Synthesis of tiazofurin (TAD) analogues with fluorinated adenosine moieties.
• Evaluation of inhibitory activity against IMPDH and alcohol dehydrogenase.
• Conformational analysis of fluorinated adenosine derivatives.

Main Results:

• C-NAD and C-PAD effectively inhibited IMPDH.
• C-NAD also potently inhibited alcohol dehydrogenase, while C-PAD did not.
• Fluorinated adenosine derivatives (TAD-analogues) showed potent inhibition of IMPDH type II.
• These derivatives exhibited weak inhibitory activity against alcohol dehydrogenase.
• Conformationally restricted nicotinamide riboside derivatives were synthesized.

Conclusions:

• Novel NAD-analogues, particularly fluorinated TAD derivatives, are potent inhibitors of IMPDH type II.
• These compounds hold potential as selective anticancer agents by targeting IMPDH in neoplastic cells.
• Further development of conformationally restricted analogues may lead to highly selective enzyme inhibitors.