ABSTRACT
A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation.
Subject(s)
Antineoplastic Agents/pharmacology , Carrier Proteins/antagonists & inhibitors , DNA Helicases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , ATPases Associated with Diverse Cellular Activities , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carrier Proteins/metabolism , Cell Proliferation/drug effects , DNA Helicases/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HCT116 Cells , HL-60 Cells , Humans , KB Cells , MCF-7 Cells , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Vitamin D receptor (VDR) antagonists have therapeutic potential in treatment of allergic conditions and hypercalcemia driven by granulomatous diseases. We have identified an o-aminoanilide analogue of the hormonal form of vitamin D with a dienyl side chain that functions as a strong VDR antagonist. Modeling studies indicate that antagonism arises from side chain rigidity, when compared to a more flexible saturated analogue, which interferes with H12 folding/alignment.
Subject(s)
Anilides/chemical synthesis , Calcitriol/analogs & derivatives , Calcitriol/chemical synthesis , Receptors, Calcitriol/antagonists & inhibitors , Anilides/pharmacology , Binding, Competitive , Calcitriol/pharmacology , Cell Line, Tumor , Cytokines/biosynthesis , Fluorescence Polarization , Humans , Models, Molecular , Receptors, Calcitriol/agonists , Stereoisomerism , Steroid Hydroxylases/biosynthesis , Structure-Activity Relationship , Vitamin D3 24-Hydroxylase , Thymic Stromal LymphopoietinABSTRACT
Incorporation of zinc-binding groups into the side-chain of 1alpha,25-dihydroxyvitamin D(3) (1,25D) fully bifunctional hybrid molecules which act both as vitamin D receptor agonists and histone deacetylase inhibitors. These bifunctional hybrids display in vitro antiproliferative activity against the AT84 squamous carcinoma cell line while lacking the in vivo hypercalcemic effects of 1,25D.
Subject(s)
Antineoplastic Agents/chemistry , Histone Deacetylase Inhibitors/chemistry , Receptors, Calcitriol/agonists , Vitamin D/analogs & derivatives , Zinc/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Vitamin D/chemistryABSTRACT
A concise and efficient total synthesis of alkaloid narceine imide is disclosed. The key steps are based upon the sequential construction of the isoindolinone template followed by metalation and coupling with an isoquinolinium salt. Subsequent E1cb elimination enables the creation of the arylmethylene unit with the concomitant formation of the dimethylaminoethyl chain and ultimate deprotection completes the synthesis of the natural product.