Duong Tien Anh (Hanoi University of Pharmacy), Doan Thanh Hieu (Thai Nguyen University of Medicine and Pharmacy), Tran Diem Huong (Hanoi University of Pharmacy), Nguyen Tran Phuong Linh (Hanoi University of Pharmacy) Instructors: Nguyen Hai Nam, Ph.D., Professor (Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy) Phan Thi Phuong Dung, Ph.D., Associate Professor (Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy) Background Molecular target-based approach has become a mainstream in new drug design and development nowadays, including the field of anticancer drugs. Among many protein targets currently used for the design of novel anticancer agents, histone deacetylases (HDAC) emerge as very attractive one. To date, at least five HDAC inhibitors have been approved for use to treat several types of cancer. These include suberoylanilide hydroxamic acid (SAHA), romidepsin, belinostat, panobinostat, and chidamide. Addition, quinazolin-4(3H)-one moiety is a common scaffold found in many diverse biological compounds. The quinazoline system, inparticular, has been present as a core structure in a number of tyrosine kinase inhibitors and anticancer agents (e.g. gelfitinib, erlotinib). Inspired by these results, we expanded our design to the new series of N-hydroxybenzamides and N-hydroxypropenamides incorporating a quinazolin-4(3H)-one moiety as a capping group. The primary concern of this research is design, synthesis of N-hydroxybenzamides and N-hydroxypropenamides series incorporating quinazolin-4(3H)-ones. Then the synthesized compounds were evaluated their HDAC inhibitory ability and cytotoxicity against three human cancer cell lines, including SW620, PC3, and NCI-H23.
Trang 1DESIGN, SYNTHESIS, AND EVALUATION OF NOVEL
N-HYDROXYBENZAMIDES/N-HYDROXYPROPENAMIDES INCORPORATING QUINAZOLIN-4(3H)-ONES AS HISTONE
DEACETYLASE INHIBITORS AND ANTITUMOR AGENTS
Duong Tien Anh (Hanoi University of Pharmacy), Doan Thanh Hieu (Thai Nguyen University of Medicine and Pharmacy), Tran Diem Huong (Hanoi University of Pharmacy), Nguyen Tran Phuong Linh (Hanoi University of Pharmacy)
Instructors:
Nguyen Hai Nam, Ph.D., Professor (Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy)
Phan Thi Phuong Dung, Ph.D., Associate Professor (Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy)
Background
Molecular target-based approach has become a mainstream in new drug design and development nowadays, including the field of anticancer drugs Among many protein targets currently used for the design of novel anticancer agents, histone deacetylases (HDAC) emerge as very attractive one To date, at least five HDAC inhibitors have been approved for use to treat several types of cancer These include suberoylanilide hydroxamic acid
(SAHA), romidepsin, belinostat, panobinostat, and chidamide Addition,
quinazolin-4(3H)-one moiety is a common scaffold found in many diverse biological compounds The quinazoline system, inparticular, has been present as a core structure in a number of tyrosine kinase inhibitors and anticancer agents (e.g gelfitinib, erlotinib) Inspired by these results,
we expanded our design to the new series of hydroxybenzamides and N-hydroxypropenamides incorporating a quinazolin-4(3H)-one moiety as a capping group The primary concern of this research is design, synthesis of N-hydroxybenzamides and
N-hydroxypropenamides series incorporating quinazolin-4(3H)-ones Then the synthesized
compounds were evaluated their HDAC inhibitory ability and cytotoxicity against three human cancer cell lines, including SW620, PC3, and NCI-H23
Materials and methods
Chemistry
All reagents and solvents were purchased from Sigma-Aldrich (USA) or Merck Solvents were used directly as purchased unless otherwise indicated TLC which was performed using Whatman® 250 mm Silica Gel GF Uniplates Melting points were measured using a Gallenkamp Melting Point Apparatus (UK) and are uncorrected Nuclear magnetic resonance spectra were recorded on a Bruker 500 MHz spectrometer with
DMSO-d 6 as solvent unless otherwise indicated Tetramethylsilane was used as an internal standard Chemical shifts are reported in parts per million (ppm), downfield from tetramethylsilane Mass spectra were recorded on LC-MSD-Trap-SL mass spectrometer for ESI
The synthesis of N-hydroxybenzamides/propenamides series incorporating
quinazolin-4(3H)-ones (4, 8, 10) was carried out as illustrated in Schemes 1-3
Scheme 1 Synthesis of N-hydroxybenzamides incorporating quinazolin-4(3H)-one (4a-h)
Trang 2Scheme 2 Synthesis of N-hydroxybenzamides incorporating 2-methylquinazolin-4(3H)-one (8a-d)
Scheme 3 Synthesis of N-hydroxypropenamides incorporating quinazolin-4(3H)-one (10a-d)
Bioactivity
The HDAC enzymes (Hela cell nuclear extract) were purchased from Enzo Life Sciences Inc (Farmingdale, New York, USA) The HDAC enzymatic assay was performed using a Fluorogenic HDAC Assay Kit (Enzo Life Sciences Inc.) according to the manufacturer’s instructions
The cytotoxicity of the synthesized compounds was evaluated against three human cancer cell lines, including SW620 (colon cancer), PC3 (prostate cancer), and NCI-H23 (lung cancer) The IC50 values were calculated using a Probits method
Results
Chemistry:
+ The targeted hydroxamic acids (4, 8, 10) were synthesized via three or four step
pathway, as illustrated in Schemes 1-3
+ The purity of targeted compounds were determined based on TLC and the value of melting point range
+ The structures of the synthesized compounds were determined straightforwardly based on analysis of spectroscopic data, including IR, MS, 1H and 13C NMR
Bioactivity:
In general, the synthesized compounds exhibited good HDAC inhibitory effects with IC50 values in a sub-micromolar range in most cases The synthesized compounds have potent cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI-H23 (lung cancer)
Conclusion
In conclusion, we have reported two series of hydroxybenzamides and N-hydroxypropenamides incorporating quinazolin-4(3H)-one moiety with strong HDAC
inhibitory effects and potent cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI-H23 (lung cancer) The
results we obtained from this study again confirm that quinazolin-4(3H)-one could well
serve as a capping group for HDAC inhibitors
Keywords: Histone deacetylase (HDAC), hydroxamic acids, quinazolin-4(3H)-one