In silico, Synthesis and Biological Investigations of Pyrrolo[3,4-C] Pyrrole Hydroxamic Acid Derivatives as Potential Anticancer Agents
Por:
Bahena, Luis, Cervantes, Carlos, Soto-Arredondo, Karla J., Martinez-Alfaro, Minerva, Zarco, Natanael, Garcia-Revilla, Marco A., Alcaraz-Contreras, Yolanda, Palma Tirado, Lourdes, Vazquez, Miguel A., Robles, Juvencio
Publicada:
1 oct 2017
Categoría:
Chemistry (miscellaneous)
Resumen:
Based in a general structural pharmacophore model of suberoylanilide
hydroxamic acid (commercially known as Vorinostat (c)), we synthesized a
series of new pyrrolo[3,4-c] pyrrole hydroxamic acid derivatives,
9a-c, to be tested as candidates for anti-cancer drugs. The evaluation
of their possible biological activity was assessed in two ways: a)
computational characterization from molecular calculations and quantum
reactivity descriptors and b) biological assays. Molecular docking and
density functional theory calculations were performed to assess the
binding properties of our newly synthesized pyrrolo[3,4-c] pyrrole
hydroxamic acid derivatives, employing as the biological target the
histone deacetylase isoforms available in the protein data bank.
Furthermore, to characterize the effect of changing the functional
groups that we varied while designing our drug model, and to improve the
assessment of the binding energy, conceptual density functional theory
reactivity descriptors were calculated to rationalize the capability of
the new drugs to interact with the histones active site. Our findings
show that the newly synthesized derivative, 9c, display the best
energetic coupling with the biological target and the more favorable
values of the density functional theory descriptors to interact with the
active site. The biological assay of the anti-cancer drug candidates was
done using three different techniques: i) anti-proliferative activity on
two breast cancer cell lines; ii) Histone H3 acetylation; and iii) DNA
damage. Docking studies were performed on histone deacetylase enzymes.
The biological function of these enzymes is the deacetylation of
histones. We analyze the level of histone acetylation in two cell lines.
The computational findings are in good agreement with the biological
evaluation. Our main contribution is that one of our newly synthesized
derivatives, 9c, performs better than the commercial reference
suberoylanilide hydroxamic acid.
Filiaciones:
Bahena, Luis:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
Cervantes, Carlos:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Quim, Noria Alta S-N, Guanajuato 36050, Mexico
Soto-Arredondo, Karla J.:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
Martinez-Alfaro, Minerva:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
Zarco, Natanael:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
Garcia-Revilla, Marco A.:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Quim, Noria Alta S-N, Guanajuato 36050, Mexico
Alcaraz-Contreras, Yolanda:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
Palma Tirado, Lourdes:
UNAM, Inst Neurobiol, Blvd Juriquilla 3001, Queretaro 76230, Mexico
Vazquez, Miguel A.:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Quim, Noria Alta S-N, Guanajuato 36050, Mexico
Robles, Juvencio:
Univ Guanajuato, Div Ciencias Nat & Exactas, Dept Farm, Noria Alta S-N, Guanajuato 36050, Mexico
|