Discovery and Investigation of Antiproliferative and Apoptosis-Inducing Properties of New Heterocyclic Podophyllotoxin Analogues Accessible by a One-Step Multicomponent Synthesis

Abstract

Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. On the basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, we implemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety to afford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared by a straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative properties in a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerous Jurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytes under the same treatment conditions. The ease of synthesis and encouraging biological activities make the presented library of dihydropyridopyrazoles promising new leads in anticancer drug design.

Synthesis of Novel Derivatives Bearing Heterocycles-Tetrahydronaphthalene Conjugates for Antimicrobial and Antiviral Evaluation

“…The formed precipitate was filtrated, dried, and recrystallized from the proper solvent to give title compound 17. (18) A mixture of cyanoacetohydrazides 1 (0.70 g, 0.003 mol), phenylisothiocynate (0.36 g, 0.003 mol) and elemental sulfur (0.10 g, 0.003 mol) in dioxane (20 ml) containing triethylamine (1 ml) was refluxed for 6 hr. After cooling the formed precipitate was filtrated, dried, and recrystallized from the proper solvent to give title compound 18.…”

“…Moreover, pyrazoles occupy an important position in medicinal chemistry with having a wide range of bioactivities such as antibacterial (17) , anticancer (18) , antidepressant (19) , anticonvulsant (20) and antipyretic (21) . A number of hydrazidehydrazone derivatives (22) have been claimed to possess interesting bioactivity such as antibacterial, antifungal (23) , anticonvulsant (24) , antimalarial (25) and antituberculosis (26) activities.…”

Intérêt des lignanes dans la prévention et le traitement de cancers

“…Une autre démarche vise à produire des composés de structure plus simple, efficaces en mélange racémique et pouvant donc être synthétisés facilement, cela est délicat car il semble que la stéreochimie du carbone 9 soit importante pour l'activité biologique. Toutefois Magedov et al [38] relatent l'obtention de composés racémiques capables d'induire l'apoptose de cellules de lymphome (lignée Jurkat). La compréhension des mécanismes moléculaires sous-jacents à l'interaction étoposide-TopoII et aux résistances a permis de définir des axes pour le développement de nouveaux dérivés.…”

A Green Approach to the Synthesis of Biologically Important Indeno[2,1‐e]pyrazolo[5,4‐b]pyridines via Microwave‐assisted Multi‐component Reactions in Water

“…Indeno 16 and antibacterial, 17 they are also inhibitors against prolyl hydroxylase, 18 glycogen synthase kinase-3, 19 protein kinase 20 and phosphodiesterase 4 (PDE4). 21,22 Indeno[1,2-b]pyridines, contained in many natural products, 23 exhibit antitumor, 24 antimicrobial, 25 antioxidant 26 and antidepressant 27 activities.…”