Design, Synthesis, and Anticancer Properties of 4,4‘-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone and Analogues

Abstract

4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.

NMR spectroscopic study of cyclodextrin inclusion complexes with A-007 prodrugs

“…In all of these preparations, the starting material used was the previously synthesized compound, A-007, and was prepared from commercially available starting materials following our previously described method. 1 Acetic acid derivatives of salt 2 were prepared from A-007 with ethyl 2-bromoacetate, followed by hydrolysis and acidification according to previously reported methods of preparation for similar phenol derivatives. 8 The trifluoroacetic acid salt 3TFA was prepared by the acylation of A-007 with Boc-glycine [(CH 3 ) 3 COCO-NHCH 2 CO 2 H] in the presence of dicyclohexylcarbodiimide (DCC), followed by trifluoroacetic acid (CF 3 CO 2 H) deprotection in CH 2 Cl 2 .…”

“…According to the NMR spectroscopy product was more than 96% pure and was used in next step without further purification. 1 J = 6.9 Hz), 4.31 (2H, q, J = 6.9 Hz), 1.36 (3H, t, J = 6.9 Hz), 1.34 (3H, t, J = 6.9 Hz); 13 …”

“…The solid material was separated by filtration, washed with water (3 Â 100 mL), and dried at 110°C for a few hours to afford a product that was pure by NMR spectroscopy (4.5 g, 95%). 1 tert-Butoxycarbonylamino-acetic acid (175 mg, 1 mmol), A007 (197 mg, 0.5 mmol), and dicyclohexylcarbodiimide (248 mg, 1.2 mmol) were taken in 20 mL of dry CH 2 Cl 2 . The reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight.…”

“…1) has recently completed a phase I clinical trial, where it was used as a therapeutic with the targeted treatment of advanced cancer, with minimal toxicity. 1 It was speculated that A-007 activity comes from complementary binding to lymphocyte receptors. This speculation was supported by experimental findings that indicate that A-007 interacts, presumably through the electron-rich (phenol) and the electron-poor (dinitrophenyl) moieties, with the CD45 receptor through complementary interactions.…”

Synthesis and antiviral activity evaluation of some new cyclohexylidenehydrazide derivatives of 1,3-thiazole core

“…On the other hand, several hydrazide-ketone hydrazone derivatives have been reported to possess varios biological activities (9) such as, antiviral (10), antineoplastic (11), antituberculostatic (12,13), analgesic (14), antibacterial (15), antifungal (16) activities.…”