Publications (2)6.44 Total impact
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Article: UNBS1450: A new hemi‐synthetic cardenolide with promising anti‐cancer activity
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ABSTRACT: Several reports suggest the sodium pump as an interesting oncology target, given that its subunit expression is markedly altered in cancer. By binding to the sodium pump, cardiotonic steroids, notably cardenolides, the natural high-affinity Na+/K+-ATPase ligands, elicit marked effects on cancer cell behavior and a number of studies have emphasized their potential use in oncology. Chemical modifications of 2″-oxovoruscharin (a novel cardenolide extracted from Calotropis procera) based on an understanding of the structure–activity relationship within the series, has led to the identification of UNBS1450, a molecule characterized by more potent anti-proliferative activity and lower toxicity than classic cardenolides. In aggressive and metastatic orthotopic NSCLC, refractory prostate cancer, and glioma models, UNBS1450 is more potent than tested reference compounds, including taxol, irinotecan, oxaliplatin, mitoxantrone, and temozolomide. The general mechanism of action associated with UNBS1450-mediated anti-cancer effects relates to the disorganization of the actin cytoskeleton. UNBS1450 can thus be considered both anti-proliferative (cytotoxic) and anti-migratory, given that the actin cytoskeleton is essential to cytokinesis and to cancer cell migration. UNBS1450 also induces non-apoptotic cell death processes (e.g., lysosome membrane permeabilization and autophagy) and thus may overcome major apoptosis resistance pathways responsible for the failure of therapeutics in certain cancers. UNBS1450 is currently in preclinical development and should reach Phase I clinical trials in 2008. Drug Dev Res 68:164–173, 2007. ©2007 Wiley-Liss, Inc.Drug Development Research 10/2007; 68(4):164 - 173. · 1.19 Impact Factor -
Article: 2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity.
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ABSTRACT: Amonafide (1), a naphthalimide which binds to DNA by intercalation and poisons topoisomerase IIalpha, has demonstrated activity in phase II breast cancer trials, but has failed thus far to enter clinical phase III because of dose-limiting bone marrow toxicity. Compound 17 (one of 41 new compounds synthesized) is a novel anticancer naphthalimide with a distinct mechanism of action, notably inducing autophagy and senescence in cancer cells. Compound 17 (2,2,2-trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157)) was found to have a 3-4-fold higher maximum tolerated dose compared to amonafide and not to provoke hematotoxicity in mice at doses that display significant antitumor effects. Furthermore, 17 has shown itself to be superior to amonafide in vivo in models of (i) L1210 murine leukemia, (ii) MXT-HI murine mammary adenocarcinoma, and (iii) orthotopic models of human A549 NSCLC and BxPC3 pancreatic cancer. Compound 17, therefore, merits further investigation as a potential anticancer agent.Journal of Medicinal Chemistry 09/2007; 50(17):4122-34. · 5.25 Impact Factor
