Synthesis of Novel 1,3,4-Trisubstituted Pyrazole Derivatives and Their Evaluation as Antitumor and Antiangiogenic Agents

Abstract

Several 1,3,4-trisubstituted pyrazole derivatives were synthesized and screened for their cytotoxic effect in a primary 3 tumor cell line test at 10(-4) M drug concentration. Compounds 19 and 20 reduced the growth of one or more of these cell lines to less than 32% and escalated up to evaluation in the full panel of 60 human tumor cell lines at a minimum of 5 concentrations at 10 fold dilutions. Compound N'-(1-[1-[4-nitrophenyl]-3-phenyl-1H-pyrazol-4-yl]methylene)-2-chlorobenzohydrazide 19 proved to be the most active of these derivatives with full panel median growth inhibition (GI50), total growth concentration (TGI) and median lethal concentration (LC50) mean graph mid-point (MG-MID) of 3.79, 12.5 and 51.5 microM, respectively. In addition, compounds 19, 39, 40, 41, 43, 45, 47 were tested for their antiangiogenic properties by testing their ability to inhibit human umbilical vein endothelial cells (HUVECs) proliferation, cord formation and migration in response to chemoattractant. 3-Acetyl-2-(1-(4-nitrophenyl)-3-phenylpyrazol-4-yl)-5-(4-pyridyl)-1,3,4-oxadiazoline 39 showed significant antiangiogenic profile at non-cytotoxic doses, with HUVEC proliferation inhibition IC50 of 7.60 microM, chemotaxis IC50 of 0.86 microM and was superior to the reference celecoxib 2 in both tests. Furthermore, in contrary to the references TNP-470 and celecoxib, all the tested compounds interfered with the migratory function of HUVECs in response to vascular endothelium growth factor (VEGF) rather than the endothelial cells proliferation.

The One-Step Synthesis of 3,4-Dihydropyrano[F]Chromene Derivatives in Under Grinding as an Environmentally Friendly Alternative

“…Compounds with an uracil moiety antitumor, antibacterial, antihypertensive, vasodilator, bronchiodilator, hepatoprotective, cardiotonic, and antiallergic activities. Some of them exhibit antimalarial, antifungal analgesics, and herbicidal properties [5][6][7][8][9] .…”

Synthesis and Characterization of Various Alkyl, Aryl and Hetero Aryl Substituted Hydrazines and Study of their Biological Activity

“…Many hydrazine derivatives are known to exhibit significant biological activity and several compounds with hydrazine moiety were shown to be effective for treatment of tuberculosis, Parkinson's disease and hypertension 1 .Hydrazines shows neuroprotective, antitumor antidepressant and antimicrobial properties 2,3,4,5 .…”

Synthesis and Characterization of Biologically Potent Chalcone Bearing 1,3,4-Oxadiazole Linkage

“…1,3,4-oxadiazole is commonly utilized pharmacophore has been subjected to extensive study in the recent years due to their metabolic profile and ability to engage in hydrogen bonding with receptor site. 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with a wide range of biological activities such as antiviral [10], antimicrobial [11], antineoplastic [12], fungicidal [13], anticancer [14,15], inhibition of tyrosinase [16], They are also useful intermediates in organic synthesis [17] and widely employed as electron transporting and hole-blocking materials.…”