title: Synthesis and bioactivity of novel amino-pyrazolopyridines.
abstract: Here we describe the synthesis and biological activity of novel amino-pyrazolopyridines with anti-NF-κB and pro-apoptotic potential. α-Methylene ketones were used as a starting point for synthesis of amino-pyrazolopyridine 3. The alkylidene malononitriles 1 were obtained by the Knoevenagel reaction of ketones with malononitriles. Vilsmeier-Haack reaction allowed direct access to 2-chloro-3-cyanopyridines 2. Those products, by refluxing with hydrazine hydrate, allowed cyclization to amino-pyrazolopyridines 3a-g, which were not previously described in the literature. Bioactivity results indicated that amino-pyrazolopyridines 3a, 3b and 3g induced apoptotic cell death in K562 cancer cells with an IC50 of 36.5 ± 3.9 μM, 27.6 ± 4.5 μM and 35.0 ± 2.3 μM, respectively, after 72 h. In addition, compounds 3a, 3b and 3g exerted NF-κB inhibition activity with an IC50 of 4.7 ± 1.6 μM, 6.9 ± 1.9 μM and 39.8 ± 3.9 μM, respectively, after 8 h in K562 cells activated with TNFα. Compounds 3b and 3g showed interesting differential toxicity as viability of peripheral blood mononuclear cells (PBMCs) from healthy donors remained largely unaffected by this treatment.
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea.
authors.forename: Barbora
authors.initials: B
authors.lastname: Orlikova
authors.affiliation: Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique (LIMBP), Université de Lorraine, SRSMC, Institut Jean Barriol, 1 Boulevard Arago, 57070, France; Laboratoire de Chimie Bioorganique et Analytique (LCBA), Université Hassan II Mohammedia-Casablanca, FST-Mohammedia, BP 146, 20800 Mohammedia, Morocco.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Chaouni
authors.affiliation: Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hôpital Kirchberg, 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg.
authors.forename: Marc
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: Laboratoire de Chimie Bioorganique et Analytique (LCBA), Université Hassan II Mohammedia-Casablanca, FST-Mohammedia, BP 146, 20800 Mohammedia, Morocco.
authors.forename: Mina
authors.initials: M
authors.lastname: Aadil
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea. Electronic address: marcdiederich@snu.ac.kr.
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.affiliation: Laboratoire de Chimie Bioorganique et Analytique (LCBA), Université Hassan II Mohammedia-Casablanca, FST-Mohammedia, BP 146, 20800 Mohammedia, Morocco. Electronic address: kirsch@sciences.univ-metz.fr.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007659:Ketones / Q000737:chemistry; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007659:Ketones; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C118531:pyrazolopyridine
keywords: Amino-pyrazolopyridine; Apoptosis; Cancer; Inflammation; NF-κB pathway; Vilsmeier–Haack