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PubMed2005

Synthesis and in vitro and in vivo antimycobacterial activity of isonicotinoyl hydrazones.

The purpose of this study was to prepare various isoniazid derivatives by introducing the isoniazid pharmacophore into several molecules and screening for antimycobacterial activity. Ortho-hydroxy acetophenone reacts with isoniazid to form acid hydrazones. The C-Mannich bases of the above acid hydrazones were prepared by reacting them with formaldehyde and various secondary amines. The synthesized compounds were screened against M. tuberculosis H(37)R(v) using the alamar blue susceptibility test. The synthesized compounds inhibit Mycobacterium tuberculosis strain H(37)R(v) with minimum inhibitory concentrations ranging from 0.56 to 4.61 microM. Compound N'-{1-[2-hydroxy-3-(piperazin-1-ylmethyl)phenyl]ethylidene}isonicotinohydrazide 8 was found to be the most active compound with an MIC of 0.56 microM, and was more potent than isoniazid (MIC of 2.04 microM). After 10 days of treatment, compound 8 decreased the bacterial load in murine lung tissue by 3.7-log10 as compared to controls, which was equipotent to isoniazid. The results demonstrate the potential and importance of developing new isoniazid derivatives against mycobacterial infections.

Animals↗
PubMed2000

Inhibition of in vitro lymphoproliferation by three novel iron chelators of the pyridoxal and salicyl aldehyde hydrazone classes.

The capacity of three novel iron chelators, namely 1-[N-ethoxycarbonylmethylpyridoxylidenium]-2-[2'-pyridyl]hydrazine bromide (EPH), 1-[5'-bromosalicylidene]-2-[2"-pyridyl]hydrazine (BsPH), and 1-pyridoxylidene-2-[1'-phthalazyl]hydrazine dihydrochloride (PPhH), to inhibit the proliferation of mitogen-stimulated murine lymph node cells was examined in vitro. All three are of the aryl hydrazone class, the prototype of which is pyridoxal isonicotinoyl hydrazone. The chelators inhibited lymphoproliferation at low micromolar concentrations. EPH and PPhH had an inhibitory capacity comparable to that of desferrioxamine (IC(50): 3 and 2 microM, respectively), whereas BsPH was more potent (IC(50) < 1 microM). The inhibitory effects of the chelator were not due to cell cytotoxicity and could be abrogated by pretreating the chelator with iron. Time-course studies established a site of action for the chelators at the G(1)/S phase transition. These agents warrant further investigation for their potential as immunosuppressants.

Animals↗
PubMed1999

EPR spin trapping and 2-deoxyribose degradation studies of the effect of pyridoxal isonicotinoyl hydrazone (PIH) on *OH formation by the Fenton reaction.

The search for effective iron chelating agents was primarily driven by the need to treat iron-loading refractory anemias such as beta-thalassemia major. However, there is a potential for therapeutic use of iron chelators in non-iron overload conditions. Iron can, under appropriate conditions, catalyze the production of toxic oxygen radicals which have been implicated in numerous pathologies and, hence, iron chelators may be useful as inhibitors of free radical-mediated tissue damage. We have developed the orally effective iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and demonstrated that it inhibits iron-mediated oxyradical formation and their effects (e.g. 2-deoxyribose oxidative degradation, lipid peroxidation and plasmid DNA breaks). In this study we further characterized the mechanism of the antioxidant action of PIH and some of its analogs against *OH formation from the Fenton reaction. Using electron paramagnetic resonance (EPR) with 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap for *OH we showed that PIH and salicylaldehyde isonicotinoyl hydrazone (SIH) inhibited Fe(II)-dependent production of *OH from H2O2. Moreover, PIH protected 2-deoxyribose against oxidative degradation induced by Fe(II) and H2O2. The protective effect of PIH against both DMPO hydroxylation and 2-deoxyribose degradation was inversely proportional to Fe(II) concentration. However, PIH did not change the primary products of the Fenton reaction as indicated by EPR experiments on *OH-mediated ethanol radical formation. Furthermore, PIH dramatically enhanced the rate of Fe(II) oxidation to Fe(III) in the presence of oxygen, suggesting that PIH decreases the concentration of Fe(II) available for the Fenton reaction. These results suggest that PIH and SIH deserve further investigation as inhibitors of free-radical mediated tissue damage.

Cyclic N-Oxides↗
PubMed2005

Tautomerization of methyldiazene to formaldehyde-hydrazone in ruthenium and osmium complexes.

Mixed-ligand hydrazine complexes [M(CO)(RNHNH2)P4](BPh4)2 (1, 2) [M = Ru, Os; R = H, CH3, C6H5; P = P(OEt)3] with carbonyl and triethyl phosphite were prepared by allowing hydride [MH(CO)P4]BPh4 species to react first with HBF4.Et2O and then with hydrazines. Depending on the nature of the hydrazine ligand, the oxidation of [M(CO)(RNHNH2)P4](BPh4)2 derivatives with Pb(OAc)4 at -30 C gives acetate [M(kappa1-OCOCH3)(CO)P4]BPh4 (3a), phenyldiazene [M(CO)(C6H5N=NH)P4](BPh4)2 (3c, 4c), and methyldiazene [M(CO)(CH3N=NH)P4](BPh4)2 (3b, 4b) derivatives. Methyldiazene complexes 3b and 4b undergo base-catalyzed tautomerization of the CH3N=NH ligand to formaldehyde-hydrazone NH2N=CH2, giving the [M(CO)(NH2N=CH2)P4](BPh4)2 (5, 6) derivatives. Complexes 5 and 6 were characterized spectroscopically and by the X-ray crystal structure determination of the [Ru(CO)(NH2N=CH2)[P(OEt)3]4](BPh4)2 (5) derivative. Acetone-hydrazone [M(CO)[NH2N=C(CH3)2]P4](BPh4)2 (7, 8) complexes were also prepared by allowing hydrazine [M(CO)(NH2NH2)P4](BPh4)2 derivatives to react with acetone.

Journal Article↗
PubMed2004

Gas-phase kinetics and mechanism of the reactions of protonated hydrazine with carbonyl compounds. Gas-phase hydrazone formation: kinetics and mechanism.

The gas-phase reactions of protonated hydrazine (hydrazinium) with organic compounds were studied in a selected ion flow tube-chemical ionization mass spectrometer (SIFT-CIMS) at 0.5 Torr pressure and approximately 300 K and with hybrid density functional calculations. Carbonyl and other polar organic compounds react to form adducts, e.g., N(2)H(5)(+)(CH(3)CH(2)CHO). In the presence of neutral hydrazine, aldehyde adducts react further to form protonated hydrazones, e.g., CH(3)CH(2)CH[double bond]HNNH(2)(+) from propanal. Using deuterated hydrazine (N(2)D(4)) and butanal, we demonstrate that the gas-phase ion chemistry of hydrazinium and carbonyls operates by the same mechanisms postulated for the reactions in solution. Calculations provide insight into specific steps and transition states in the reaction mechanism and aid in understanding the likely reaction process upon chemical or translational activation. For most carbonyls, rate coefficients for adduct formation approach the predicted maximum collisional rate coefficients, k approximately 10(-9) cm(3) molecule(-1) s(-1). Formaldehyde is an exception (k approximately 2 x 10(-11) cm(3) molecule(-1) s(-1)) due to the shorter lifetime of its collision complex. Following adduct formation, the process of hydrazone formation may be rate limiting at thermal energies. The combination of fast reaction rates and unique chemistry shows that protonated hydrazine can serve as a useful chemical-ionization reagent for quantifying atmospheric carbonyl compounds via CIMS. Mechanistic studies provide information that will aid in optimizing reaction conditions for this application.

Journal Article↗
PubMed2001

Palladium-catalyzed allylic alkylation using chiral hydrazones as ligands.

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (4) with a dimethyl malonate-BSA-LiOAc system and its derivatives has been successfully carried out in the presence of a new chiral hydrazone ligands such as 2-(diphenylphosphino)benzaldehyde SAMP hydrazone (DPPBA-SAMP) (3a) in high yields with high enantioselectives.

Journal Article↗
PubMed2003

Tandem carbon-carbon bond-forming radical addition-cyclization reaction of oxime ether and hydrazone.

The novel tandem radical addition-cyclization of oxime ethers and hydrazones intramolecularly connected with the alpha,beta-unsaturated carbonyl group is described. The radical reaction of oxime ethers 1, 2, and 4 connected with acryloyl and methacryloyl moieties proceeded smoothly to give the heterocycles via a tandem C-C bond-forming process. The tandem reaction of hydrazone 5 took place in the presence of Zn(OTf)(2) as a Lewis acid to give the trans-cyclic product 17 without the formation of the cis-isomer. The diastereoselective radical addition-cyclization reaction of chiral oxime ether 19 was also studied. The tandem reaction of 19 proceeded smoothly even in aqueous media, providing the novel method for asymmetric synthesis of gamma-butyrolactones and beta-amino acid derivatives.

Journal Article↗
PubMed2003

New trimethylaluminum-induced mannich-type reaction of hydrazones.

Trimethylaluminum addition to N-monoalkyl or N-monoaryl hydrazones followed by aldehyde addition leads to the formation of N-alkylated hydrazones in a new formal Mannich-type process. Addition compounds were also obtained in moderate yields with ketones. The mechanism as well as possible intermediates involved in the reaction are discussed.

Journal Article↗
PubMed2000

The effect of varying substituents on the equilibrium distribution and conformation of macrocyclic steroidal N-acyl hydrazones

The equilibrium distribution of deoxycholate-based macrocyclic N-acyl hydrazones is dependent upon the nature of the substituents at the 3- and 12-position. These substituents can also influence the preferred conformation of the macrocycles. The conversion of pure cyclic dimer and trimer into a mixture of both components, in the presence of trifluoroacetic acid, has been demonstrated and an X-ray crystal structure obtained of a macrocyclic N-acyl hydrazone dimer.

Journal Article↗
PubMed2006

Discotic liquid crystalline hydrazone compounds: synthesis and mesomorphic properties.

[reaction: see text] 1,3,5-Trisacetoacetamidobenzene with three 1,3-diketo groups was synthesized by the reaction of 1,3,5-triaminobenzene with diketene. Discotic hydrazone compounds were prepared by the diazo coupling reaction between 1,3,5-trisacetoacetamidobenzene and diazonium salts of 4-alkyloxyphenylamines. The compounds existed in hydrazone forms exclusively, being stabilized by the intramolecular hydrogen bonds, and showed discotic nematic or columnar hexagonal mesophases.

Journal Article↗
PubMed2000

NaH-mediated one-pot cyclocondensation of 6-nitroquinoline with aromatic hydrazones to form

[reaction: see text] 6-Nitroquinoline undergoes direct cyclocondensation with aromatic hydrazones in the presence of sodium hydride in DMF at -10 degrees C, giving the corresponding 3-aryl-1(3)H-pyrazolo[3,4-f]quinolines and/or 3-aryl[1.2.4]triazino[6,5-f]quinolines in low to moderate yield. The mode of cyclocondensation is considerably dependent on the electronic nature of ring substituent of hydrazones, an electron-donating substituent favoring the formation of the latter heterocycles.

Journal Article↗
PubMed1998

Analogues of pyridoxal isonicotinoyl hydrazone (PIH) as potential iron chelators for the treatment of neoplasia.

Cancer cells have a high requirement for iron (Fe) as it plays a crucial role in a variety of metabolic processes including energy production and DNA synthesis. Studies in vitro and in vivo have demonstrated that the Fe chelator in current clinical use, desferrioxamine (DFO), can effectively inhibit the growth of some neoplasms, including leukemia and neuroblastoma. Unfortunately, DFO suffers from a number of serious disadvantages, including its high cost, the need for prolonged subcutaneous infusion (12-24 h/day, 5-6 nights/week), and its poor intestinal absorption precluding oral administration. Hence, the development of more effective Fe chelators is necessary. The Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), was initially identified as a ligand that showed high activity at mobilizing Fe from cells. More recently, a range of PIH analogues have been examined for their anti-proliferative effect, with several classes of these compounds showing high activity at inhibiting tumor growth in vitro. In fact, some of these hydrazones, particularly those derived from 2-hydroxy-1-naphthylaldehyde, showed comparable activity to the cytotoxic drugs cis-platin and bleomycin. In this review the role of Fe in cellular proliferation will be examined followed by a description of the most recent studies using the PIH analogues as effective anti-proliferative agents. Further studies in vivo with these Fe chelators are essential to determine their potential as chemotherapeutic agents.

Animals↗
PubMed1999

The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: the effect of the ligands on molecular targets involved in proliferation.

We have identified specific iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class that are far more effective ligands than desferrioxamine (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood 89:3025, 1997). In the present study, we have compared the effect of DFO and one of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 311) on molecular targets involved in proliferation. This was performed to further understand the mechanisms involved in the antitumor activity of Fe chelators. Ligand 311 was far more active than DFO at increasing Fe release from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells and preventing Fe uptake from transferrin. Like DFO, 311 increased the RNA-binding activity of the iron-regulatory proteins (IRPs). However, despite the far greater Fe chelation efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was not inhibited by cycloheximide. These results suggest that, irrespective of the Fe chelation efficacy of a ligand, an increase IRP-RNA binding activity occurred via a time-dependent step that did not require protein synthesis. Further studies examined the effect of 311 and DFO on the expression of p53-transactivated genes that are crucial for cell cycle control and DNA repair, namely WAF1, GADD45, and mdm-2. Incubation of 3 different cell lines with DFO or 311 caused a pronounced concentration- and time-dependent increase in the expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the distinct differences in Fe chelation efficacy and antiproliferative activity of DFO and 311, much higher concentrations of DFO (150 micromol/L) than 311 (2.5 to 5 micromol/L) were required to markedly increase GADD45 and WAF1 mRNA levels. The increase in GADD45 and WAF1 mRNA expression was seen only after 20 hours of incubation with the chelators and was reversible after removal of the ligands. In contrast to the chelators, the Fe(III) complexes of DFO and 311 had no effect on increasing GADD45 and WAF1 mRNA levels, suggesting that Fe chelation was required. Finally, the increase in GADD45 and WAF1 mRNAs appeared to occur by a p53-independent pathway in SK-N-MC and K562 cells, because these cell lines lack functional p53. Our results suggest that GADD45 and WAF1 may play important roles in the cell cycle arrest observed after exposure to these chelators.

Antineoplastic Agents↗
PubMed1999

Action of free radical in podophyllic acid piperindyl hydrazone nitroxide radical on its antitumor activity and toxicity.

AIM: To study the action of free radical in the spin-labeled podophyllotoxin derivative, podophyllic acid piperindyl hydrazone nitroxide radical (GP-1) on its antitumor activity and toxicity, by comparison with those of its free radical reduced product, podophyllic acid piperindyl hydrazone (GP-1-H). METHODS: After treatment with GP-1 and GP-1-H, the inhibitory effects on the growth of mouse transplantable tumors were determined; MTT formazan formation, [3H]deoxythymidine ([3H]TdR) incorporation, cell cycle progression, and mitotic index of SGC-7901 or L1210 cells were measured; the acute toxicity and immune function of mice were assayed. RESULTS: At doses of 1/6 and 1/12 LD50, the inhibitory rates against Lewis lung carcinoma were 60.3% and 42.1% (GP-1), 38.9% and 10.3% (GP-1-H), respectively; more effective antitumor activity of GP-1 against P388, HePS, and S-180 than that of GP-1-H were found. In vitro, GP-1 exhibited more powerful inhibitory effects on the proliferation and DNA synthesis of SGC-7901 and L1210 cells than GP-1-H. GP-1 and GP-1-H arrested the L1210 cells at G2/M phase with a corresponding decrease of the cells in G1 phase, and increased the mitotic index of the cells; but the effects of GP-1-H were weaker than those of GP-1. After treatment with doses of 1/4 and 1/8 LD50 for 5 d, no significant difference on immune function of mice between GP-1 and GP-1-H was found. CONCLUSION: GP-1 had more powerful antitumor activities than GP-1-H. The free radical in the spin-labeled podophyllotoxin derivative, GP-1, played an important role in its antitumor activity.

Adenocarcinoma↗
PubMed2006

[Synthesis of 4-(benzeneazo) salicyladelhyde hydrazones and study on their spectral properties].

4-(benzeneazo) salicyladelhyde was synthesized with aniline and salicylaldehyde. Benzoylhydrazine and p-hydroxybenzoylhydrazine were synthesized using the reaction of ethyl benzoate and methyl p-hydraxy benzoate with hydrazine hydrate. Four novel 4-(benzeneazo) salicyladelhyde hydrazones were synthesized using the reaction of 4-(benzeneazo) salicyladelhyde with benzoylhydrazine, p-hydroxybenzoylhydrazine, phenylhydrazine, and isonicotinyl hydrazine respectively. IR, UV and the fluorescence spectrum of 4-(benzeneazo) salicyladelhyde hydrazones were studied.

English Abstract↗
PubMed1987

[Synthesis and antitumor properties of rubomycin 13-cyclohexylidene hydrazone].

Rubomycin 13-cyclohexylidene hydrazone (RCH) was synthesized by interaction of rubomycin 13-hydrazone with cyclohexane. Antitumor activity of RCH was studied in comparison to that of the initial rubomycin on mice with ascitic lymphadenosis NK/Ly, Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388, solid lymphosarcoma LIO-1 and sarcoma 180. It was shown that RCH was actually equal to rubomycin by its selective activity against lymphadenosis NK/Ly and sarcoma 180 on its 4- and 2-fold intravenous administration, respectively. RCH was superior to rubomycin by its selective activity against lymphosarcoma LIO-1 and Ehrlich carcinoma and was more efficient in treatment of hemocytoblastosis La. RCH was inferior to rubomycin by its efficacy in treatment of lymphadenosis NK/Ly on its 2-fold oral administration and against leukemia P-388 on its 2-fold intravenous administration. Comparison of RCH with an analogous derivative of carminomycin showed that analogous changes in the chemical structure of rubomycin and carminomycin induced different changes in the chemotherapeutic properties of the initial substances.

Animals↗
PubMed1986

Synthesis and antifertility activity of some new fluorine containing 2-([2-(fluoroaryl)-1H-indol-3- yl]methylene)hydrazinecarbothioamides and 2-(fluoroaryl)-([5-(substituted benzylidene)-4-oxo-2-thiazolidinylidene]hydrazone)- 1H-indole-3-carboxaldehydes.

New fluorine containing 2-(fluoroaryl)-1H-indole-3-carboxaldehydes have been synthesized and subjected to reaction with thiosemicarbazide to give corresponding 2-([2- (fluoroaryl)-1H-indol-3-yl]methylene)hydrazinecarbothiamides which were cyclized in the presence of chloroacetic acid, sodium acetate and substituted benzaldehydes to 2-(fluoroaryl)-([5- (substituted benzylidene)-4-oxo-2-thiazolidinylidene]hydrazone)- 1H-indole-3-carboxaldehydes as potential antifertility agents. In preliminary screening, 2-(4'-fluorophenyl)- ([5-(methylene-3,4-dioxyphenyl)-4-oxo-2- thiazolidinylidene]hydrazone)-1H-indole-3-carbocaldehyde exhibited pronounced antifertility activity. All these new compounds have been characterized by analytical and spectral (IR, PMR, MS) studies.

Animals↗
PubMed1999

Investigations on the mechanism of action of the novel antitumor agents 2-benzothiazolyl, 2-benzoxazolyl, and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine.

2-Acetylpyridine hydrazone derivatives of benzothiazole, benzoxazole, and benzimidazole were found to exhibit potent cytotoxic activity against the growth of suspended leukemia and lymphomas. They were also active in a number of solid tumor screens, e.g. HeLa uterine carcinoma, SOS bone osteosarcoma, lung MB9812, lung A549, Mcf-7 breast growth. In L1210 lymphoid leukemia cells the compounds preferentially inhibited RNA synthesis followed by DNA synthesis at 100 microM after 60 min. The reduction of de novo purine synthesis by the compounds at the regulatory sites PRPP-amido transferase, IMP dehydrogenase and dihydrofolate reductase was responsible for the suppression of nucleic synthesis. Other minor sites where the agents have metabolic effects were thymidylate synthetase and thymidine kinase which would be additive with the overall inhibition of cell growth. The ct-DNA studies suggest that the compounds also interacted with the DNA molecule itself, probably affecting template activity.

Animals↗