Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides.
We describe the synthesis of a novel series of bis-basic substituted benzamides and their relative potency in inhibiting rat brain protein kinase alpha (PKC alpha) activity. None of the compounds inhibited enzyme activity via the catalytic domain but several did via the regulatory domain at 1-5 microM concentrations. Inhibition was comparable to that of several di- and triphenylacrylonitriles and triphenylethylenes. According to a multivariate factor (correspondence) analysis of QSAR descriptors, hydrophobicity (log p) and hydration energy were the most discriminant descriptors, much more so than molecular mass, molar refractivity, polarizability, molecular volume and solvent-accessible surface. Inhibitory activity was correlated with high hydrophobicity and low hydration energy. The higher potency of GL9 (N,N'-oxalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide]) that differed from its congener (GL25) by the presence of an oxamide rather than succinamide moiety was tentatively explained by the greater negative charges associated with the carbonyl groups of its oxamide residue. The higher potency of GL22 (N,N'-tere-phthalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide ] in which an aromatic ring is inserted between two benzamide moieties in para, para' rather than ortho, ortho' positions as in GL23 might be due to a planar conformation facilitating membrane insertion. In conclusion, correspondence analysis is a neat way of highlighting similarities and differences in molecular properties (QSAR descriptors and potency). Therapeutic doses of many classes of drug might interfere with the regulatory domain of PKC alpha if, like our test-compounds, they have basic side-chain(s), high hydrophobicity, low hydration energy, a planar conformation and/or a highly charged reactive (oxamide) moiety.
Gilbert
J
J
CNRS-SIRCOB, Université de Versailles/St. Quentin-en-Yvelines, France.
Cheminant
M
M
Bignon
E
E
Pons
M
M
Ojasoo
T
T
Doré
J C
JC
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D020134:Catalytic Domain / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D015999:Multivariate Analysis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D001549:Benzamides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha