Journal
LETTERS IN DRUG DESIGN & DISCOVERY
Volume 16, Issue 5, Pages 597-605Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1570180816666181220121042
Keywords
Anilines; secondary amines; myrtenal; perillyl aldehyde; terpenes; cancer; molecular modeling; chemical space
Categories
Funding
- Russian Foundation for Basic Research [16-33-60028, 18-44-540023 r a]
- Program of Fundamental Scientific Research of the State Academies of Sciences for 2017-2020 [VI. 57.1.2, 0309-2016-0001]
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Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1(TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there arc compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential. Methods: Structures of all the synthesized compounds were confirmed by H-1 and C-13 NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor. Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 mu M. The highest activity was found for (-)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue. Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.
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