Domain-Structured N,N-Derivatized Hydrazines as Inhibitors of Ribonucleoside Diphosphate Reductase:  Redox-Cycling Considerations

Abstract

Eight analogues of 1-[5-halogenosalicylidene]-2-[2'-pyridinoyl]hydrazine and -[2'-pyridyl]hydrazine, four of 1-[pyridoxylidene]-2-[2'-pyridinoyl]hydrazine, seven of 1-[pyridoxylidene]-2-[2'-pyridyl]hydrazine, and one each of 1, 2-bis[pyridoxylidene]diaminoethane and bis[pyridoxylidenehydrazino]phthalazine were synthesized. Their solutions in DMF were assayed for activity against the metalloenzyme ribonucleoside diphosphate reductase (RdR), prepared from a subcutaneously growing murine tumor (sarcoma 180) implanted in B6D2F3 male mice. The 14C-labeled CDP reductase was assayed by the modified method of Takeda and Weber, in which [14C]cytidine was separated from deoxycytidine by thin-layer chromatography (TLC) on cellulose foil. Distribution of radioactivity was assessed with an automatic TLC linear analyzer. Of the 31 compounds tested, 13 were essentially inactive, 7 were highly active against RdR, and the remaining 20 were slightly more active than hydroxyurea (used as a reference compound). The mechanism of inhibition is discussed in terms of three alternative pathways, initiated by sequestration of iron embedded in the R1 subunit of the metalloenzyme to form a C-centered chelate radical (via redox cycling). Alternatively, the latter could either reduce the tyrosyl radical or intercept radicals generated in the reduction process.

Synthesis of Some New Chiral Tricyclic and Macrocyclic Pyridine Derivatives as Antimicrobial Agents

“…To a solution of N 2 ,N 2 -(pyridine-2,6-dicarbonyl) diaminoacid hydrazides (2a-c) [3] (1 mmol) in dichloromethane (50 ml) at (−10 • C) with stirring, 2,6-pyridine-dicarbonyl dichloride (4) [14,15] 6.7,15,16,19,25,5,8,14,17, [3,19,1,1 9,13 ]hexacosa-1 (24), 9,11,13,21,23- A mixture of bis-hydrazides (2a-c) (1 mmol) and 2,6diacetylpyridine (6) [17] (0.163 g, 1 mmol) in absolute ethanol (100 ml) was refluxed for 6 h. The reaction mixture was concentrated under reduced pressure, the solid formed was collected by filtration, washed with ether and purified by crystallization to give the tricyclooctaene derivatives (7a-c), respectively. -8,19-dimethyl-3,6.7,15,16,19,25,26octaaza-2,5,17,20-tetraoxotricyclo [3,19,1,1 9,13 ]hexacosa-1(24), 7,9,11,13,15,21,23- 4,6.7,15,16,19,25,5,17,19,1,1 9,13 ]hexacosa-1(24), 7,9,11,13,15,21,23- 7,9,11,13,15,21,23- …”

“…4,17-Isopropyl-3,6.7,15,16,19,25,26-octaaza-2,5, 17,20-tetraoxotricyclo[3,19,1,1 9, 13 ]hexacosa-1(24), 7,9,11,13,15,21,23- 4,6.7,15,16,19,25,5,17, [3,19,1,1 9,13 ]hexacosa-1 (24), 7,9,11,13,15,21,23- 4,6.7,15,16,19,25,5,17, [3,19,1,1 9,13 ]hexacosa-1 (24),7,9,11,13,15,21,23- 4,6.7,14,15,18,5,16,19,18,1,1 9,12 ]pentacosa-1(23), 7,9,11,13,20,22- 3,6.7,14,15,18,24-heptaaza-2,5,16, 19,25-pentaoxotricyclo [3,18,1,1 9,12 ]pentacosa-1(23), 7,9,11,13,20,22- -3,6.7,14,15,18,24-heptaaza-2,5,16, 19,25-pentaoxotricyclo [3,18,1,1 9,12 ]pentacosa-1(23), 7,9,11,13,20,22- A solution of N 2 ,N 2 -(pyridine-2,6-dicarbonyl)diaminoacid hydrazides (2a,b) [3] (1 mmol) in cold (−5 • C) mixture of 5N hydrochloric acid (2 ml), glacial acetic acid (3 ml) and water (10 ml) was stirred for 15 min. Aqueous sodium nitrite (0.2 g, 2 ml water) was added in one portion and the mixture was stirred for 0.5 h. The azide formed in situ was extracted with cold dichloromethane (60 ml).…”

“…In continuation of our previous investigations [2,3], we have recently reported the synthesis and biological activity screening of some dipicolinic acid bis-L-amino acid hydrazide derivatives [3] and their corresponding acids [4]. The compounds of this kind have been given considerable attention as inhibitors of ribonucleoside diphosphate reductase [5]. Synthetic macrocyclic peptides are still subject of intensive research with respect to their therapeutic applications [6] as well as their binding properties [7].…”

Synthesis and Antitubercular Activity of Heteroaromatic Isonicotinoyl and 7-Chloro-4-Quinolinyl Hydrazone Derivatives

“…Moreover, it is probable that Mn 3+ ions could facilitate the formation of isonicotinic acyl radicals and KatG participates in isoniazid activation by increasing the rate of the conversion of Mn 2+ to Mn 3+ ions. Due to the ability of hydrazone derivatives in metal chelation [9] and generation of metal ion-induced radical intermediates [10,11,12], we decided to investigate the potential anti-TB activity of a series of heteroaromatic hydrazones derived from INH (3a-f and 4a-b, see Scheme 1). Another aim of this article is to compare the biological activity of the INH derivatives to a series of heteroaromatic 7-chloro-4-quinolinylhydrazones (5a-f and 6a-b, see Scheme 1).…”