Ethyl 1,8-naphthyridone-3-carboxylates downregulate human papillomavirus-16 E6 and E7 oncogene expression

Area of Science:

• Oncology
• Virology
• Medicinal Chemistry

Background:

• Cervical cancer (CC) is strongly linked to high-risk human papillomavirus (HPV) infections.
• Viral E6 and E7 oncoproteins are key drivers of HPV-induced carcinogenesis.

Purpose of the Study:

• To identify novel compounds that inhibit HPV transcription.
• To develop potential therapeutic agents for HPV-associated cervical cancer.

Main Methods:

• Screening of an in-house compound library using a cell-based high-throughput assay.
• Synthesis and evaluation of 1,8-naphthyridone analogues for their ability to downregulate HPV E6 and E7 transcripts.
• In vitro uptake studies to assess compound mechanism.

Main Results:

• A 1,8-naphthyridone derivative (compound 1) was identified that inhibits HPV long control region transcription.
• Synthesized analogues showed increased potency in downregulating E6 and E7 transcripts in HPV-16-positive CaSki cells.
• Ethyl carboxylate esters at the C-3 position were crucial for activity, and these compounds did not act as prodrugs.

Conclusions:

• 1,8-naphthyridones are promising starting points for developing new treatments for HPV-induced cervical cancer.
• The identified compounds offer a novel strategy to target viral oncoprotein expression.