RT Journal Article
T1 A new family of Jumonji C domain-containing KDM inhibitors inspired by natural product Purpurogallin
A1 Souto Salgado, Jose Antonio
A1 Sarno, Federica
A1 Nebbioso, Ángela
A1 Papulino, Chiara
A1 Álvarez Rodríguez, Maria Rosana
A1 Lombino, Jessica
A1 Perricone, Ugo
A1 Padova, Alessandro
A1 Altucci, Lucia
A1 Rodríguez de Lera, Ángel
K1 3207.03 Carcinogénesis
K1 2302 Bioquímica
K1 2306 Química Orgánica
AB Aberrant epigenetic modifications are involved in cancer development. Jumonji Cdomain-containing histone lysine demethylases (KDMs) are found mainly up-regulatedin breast, prostate, and colon cancer. Currently, growing interest is focusing on theidentification and development of new inhibitors able to block the activity of KDMsand thus reduce tumor progression. KDM4A is known to play a role in severalcellular physiological processes, and was recently found overexpressed in a numberof pathological states, including cancer. In this work, starting from the structure ofpurpurogallin 9aa, previously identified as a natural KDM4A inhibitor, we synthesizedtwo main sets of compound derivatives in order to improve their inhibitory activityagainst KDM4A in vitro and in cells, as well as their antitumor action. Based onthe hypothetical biogenesis of the 5-oxo-5H-benzo[7]annulene skeleton of the naturalproduct purpurogallin (Salfeld, 1960; Horner et al., 1961; Dürckheimer and Paulus,1985; Tanaka et al., 2002; Yanase et al., 2005) the pyrogallol and catechol units werefirst combined with structural modifications at different positions of the aryl ring usingenzyme-mediated oxidative conditions, generating a series of benzotropolone analogs.Two of the synthetic analogs of purpurogallin, 9ac and 9bc, showed an efficient inhibition(50 and 80%) of KDM4A in enzymatic assays and in cells by increasing levels of its specifictargets, H3K9me3/2 and H3K36me3. However, these two compounds/derivatives didnot induce cell death. We then synthesized a further set of analogs of these twocompounds with greater structural diversification. The most potent of these analogs,9bf, displayed the highest KDM4A inhibitory enzymatic activity in vitro (IC50 of 10.1 and24.37μM) in colon cancer cells, and the strongest antitumor action in several solid andhematological human cancer cell lines with no toxic effect in normal cells. Our findingssuggest that further development of this compound and its derivatives may lead to theidentification of new therapeutic antitumor agents acting through inhibition of KDM4A.
PB Frontiers in Chemistry
SN 22962646
YR 2020
FD 2020-05-25
LK http://hdl.handle.net/11093/2344
UL http://hdl.handle.net/11093/2344
LA eng
NO Frontiers in Chemistry, 8, 00312 (2020)
NO Xunta de Galicia | Ref. ED431C 2017/61
DS Investigo
RD 26-ene-2025