ABSTRACT
Ruthenium catalyzed 1,3-cycloaddition (click chemistry) of an azido moiety installed on dihydroxycumene scaffold with differently substituted aryl propiolates gave a new family of 1,4,5-trisubstituted triazole carboxylic acid derivatives that showed high affinity toward Hsp90 associated with cell proliferation inhibition, both in nanomolar range. The 1,5 arrangement of the resorcinol, the aryl moieties, and the presence of an alkyl (secondary) amide in position 4 of the triazole ring were essential to get high activity. Docking simulations suggested that the triazoles penetrate the Hsp90 ATP binding site. Some 1,4,5-trisubstituted triazole carboxamides induced dramatic depletion of the examined client proteins and a very strong increase in the expression levels of the chaperone Hsp70. In vitro metabolic stability and in vivo preliminary studies on selected compounds have shown promising results comparable to the potent Hsp90 inhibitor NVP-AUY922. One of them, (compound 18, SST0287CL1) was selected for further investigation as the most promising drug candidate.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Antineoplastic Agents/metabolism , Blotting, Western , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Computational Biology , Flow Cytometry , HSP90 Heat-Shock Proteins/metabolism , Humans , Indicators and Reagents , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Mice , Models, Molecular , Protein Binding , Resorcinols/chemical synthesis , Resorcinols/pharmacology , Ruthenium , Spectrometry, Fluorescence , Structure-Activity Relationship , X-Ray Diffraction , Xenograft Model Antitumor AssaysABSTRACT
We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na(+),K(+)-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na(+),K(+)-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency.
Subject(s)
Androstanes/chemistry , Enzyme Inhibitors/chemical synthesis , Etiocholanolone/analogs & derivatives , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Etiocholanolone/chemical synthesis , Etiocholanolone/chemistry , Etiocholanolone/therapeutic use , Guinea Pigs , Heart Failure/drug therapy , Sodium-Potassium-Exchanging ATPase/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.
Subject(s)
Etiocholanolone/analogs & derivatives , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Amines/chemistry , Animals , Etiocholanolone/chemical synthesis , Etiocholanolone/chemistry , Etiocholanolone/pharmacology , Guinea Pigs , Hydroxylation , Models, Molecular , Molecular Structure , Sodium-Potassium-Exchanging ATPase/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A small library of 2-deacetoxytaxinine J (DAT-J) 1 derivatives was synthesised and tested in vitro for their reversal activity in human mammary carcinoma MDR cell line MCF7-R. One of the new taxoids showed to be active at 0.1 microM when tested in combination with paclitaxel.
