Derivatives VII Research Articles

Exploring the cytotoxic effect and CDK-9 inhibition potential of novel sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles

Regarding the structural analysis of variable effective CDK-9 suppressors, we record the design and synthesis of two new sets of sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles with expected anticancer and CDK-9 inhibiting activity. In the designed molecules, the pyrazole ring and sulphaguanidine fragment were linked together for the first time through diazo linkers as they are expected to enhance the anticancer activity and CDK degrading interaction. All derivatives have been estimated regarding their cytotoxic activity toward three tumor cells where CDK overexpression has been reported (HePG2, HCT-116, and MCF-7). Among these, four derivatives VII, VIII, X, and XIII exerted potent cytotoxicity against the chosen tumor cells presenting IC50 range equal to 2.86–25.89 µM. As well cytotoxicity on non-cancer cells and CDK-9 inhibition assay have been also assessed for these candidates to evaluate their selectivity indices and enzyme inhibition. The 3,5-diaminopyrazole-1-carboxamide derivative XIII showed a superior combined profile as cytotoxic with high selectivity toward cancer cells (HePG2: IC50 = 6.57 µM, SI = 13.31; HCT-116: IC50 = 9.54 µM, SI = 9.16; MCF-7: IC50 = 7.97 µM, SI = 10.97). Accordingly, it has been chosen to evaluate its probable mechanistic effect both in vitro (via enzyme assay, apoptosis induction, and cell cycle study) as well as in silico (through molecular docking). Overall, this work introduces the 3,5-diaminopyrazole-1-carboxamide derivative XIII as a potent CDK-9 inhibitor candidate (IC50 = 0.16 µM) that merits further investigations for the management of breast, colorectal, and hepatic malignancies.

Molecular design, synthesis and biological evaluation of novel 1,2,5-trisubstituted benzimidazole derivatives as cytotoxic agents endowed with ABCB1 inhibitory action to overcome multidrug resistance in cancer cells

Multidrug resistance (MDR) is a leading cause for treatment failure in cancer patients. One of the reasons of MDR is drug efflux by ATP-binding cassette (ABC) transporters in eukaryotic cells especially ABCB1 (P-glycoprotein). In this study, certain novel 1,2,5-trisubstituted benzimidazole derivatives were designed utilising ligand based pharmacophore approach. The designed benzimidazoles were synthesised and evaluated for their cytotoxic activity towards doxorubicin-sensitive cell lines (CCRF/CEM and MCF7), as well as against doxorubicin-resistant cancer cells (CEM/ADR 5000 and Caco-2). In particular, compound VIII showed a substantial cytotoxic effect in all previously mentioned cell lines especially in doxorubicin-resistant CEM/ADR5000 cells (IC50 = 8.13 µM). Furthermore, the most promising derivatives VII, VIII and XI were tested for their ABCB1 inhibitory action in the doxorubicin-resistant CEM/ADR 5000 subline which is known for overexpression of ABCB1 transporters. The results showed that compound VII exhibited the best ABCB1 inhibitory activity at three tested concentrations (22.02 µM (IC50), 50 µM and 100 µM) in comparison to verapamil as a reference ABCB1 inhibitor. Such inhibition resulted in a synergistic effect and a massive decrease in the IC50 of doxorubicin (34.5 µM) when compound VII was used in a non-toxic dose in combination with doxorubicin in doxorubicin-resistant cells CEM/ADR 5000 (IC50(Dox+VII) = 3.81 µM). Molecular modelling studies were also carried out to explain the key interactions of the target benzimidazoles at the ABCB1 binding site. Overall the obtained results from this study suggest that 1,2,5-trisubstituted benzimidazoles possibly are promising candidates for further optimisation and development of potential anticancer agents with ABCB1 inhibitory activity and therefore overcome MDR in cancer cells.

The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives

The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I-VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5–50µM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models.

Structural investigation of Ca2+ antagonists benzofurazanyl and benzofuroxanyl-1,4-dihydropyridines

The structure of Ca2+ channel blockers benzofurazanyl- and benzofuroxanyl-1,4-dihydropyridines (1,4-DHPs) was investigated by an integrated NMR, X-ray diffraction and molecular graphics study. 1H- and 13C-NMR showed that all the benzofuroxan derivatives exist in solution as tautomeric mixtures. ΔG° and ΔG∗ for 4′⇄7′ and 5′⇄7′ benzofuroxanyl tautomeric equilibria were determined for the benzofuroxan derivatives VI and VII. These figures are close to those observed for other substituted benzofuroxans known from literature including DHP derivatives.The conformational domain of all the compounds was analyzed, showing two sets of energetically accessible arrangements of the heterocyclic substructure with respect to C(4)H–DHP hydrogen, antiperiplanar and synperiplanar. Rotameric preference in solution around the C(4)–C(4′) bond in benzofurazanyl derivative IV was sought by normalized transient ΔNOE spectra using interatomic distances derived from AM1 energy minimized structures. A synperiplanar fraction of ca. 75% was calculated, in keeping with results obtained by Rovnyak for Nifedipine. Finally, the solid state preferred conformation was assessed by X-ray analysis for 5′-benzofurazanyl (V) and 5′(6′)-benzofuroxanyl (VII) derivatives. The latter in the solid state prefers the 5′-form (VIIa). The pentatomic ring systems always lie on the same side of the C(4)H–DHP hydrogen. This was also found to be the case for 4′-substituted derivatives and a large number of dihydropyridine derivatives.

Synthesis of 1-(3-Azido-2,3-dideoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)thymine, 1-(2,3-Dideoxy-4-C-hydroxymethyl-α-L-glycero-pentofuranosyl)thymine and 1-(2,3-Dideoxy-4-C-hydroxymethyl-α-L-glycero-pent-2-enofuranosyl)thymine

1-(2-O-Acetyl-3,5-di-O-benzoyl-4-C-benzoyloxymethyl-α-L-arabinofuranosyl)thymine (II) was converted to 2,2'-anhydro derivative V by selective deacetylation, mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Cleavage of 2,2'-anhydro ring in compound V with hydrogen chloride or bromide afforded the respective 2'-chloro and 2'-bromo derivatives VI and VII. Reaction of compound VII with Cu/Zn couple and subsequent debenzoylation led to 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-pent-2-enofuranosyl)thymine (IX). Catalytic hydrogenation of IX gave 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-glycero-pentofuranosyl)thymine (X). Dehalogenation of compound VI with tributyltin hydride and debenzoylation afforded 1-(2-deoxy-4-C-hydroxymethyl-α-L-erythro-pentofuranosyl)thymine (XII). Tritylation of compound XII, followed by mesylation, detritylation and nucleophilic substitution with azide furnished 1-(3-azido-2,3-dideoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)thymine (XXII).

New synthesis of 2-substituted imidazo[2,1-b]thiazoles and their antimicrobial activities

4,5-Diphenyl-2-mercaptoimidazole (I) was reacted with hydrazidoyl halides IIa−d to give the S-alkyl derivatives IIIa−d. Cyclization of IIIa−d afforded imidazo[2, 1−b]-thiazole derivatives VIa,b and VII. Treatment of I with α-chloroethylacetoacetate (IV) gave ethyl 2-(4,5-diphenyl-2-imidazolinylthio)-3-keto-butyrate (V). Compound V coupled with benzenediazonium chloride to give the corresponding phenylhydrazo compound IIId. On heating V with polyphosphoric acid, cyclization took place and 2-acetyl-5,6-diphenyl-imidazo[2, 1−b]thiazol-3-one (VIII) was obtained. The compound VIII was condensed with aromatic aldehydes to yield the cinnamoyl derivatives IXa,b. The antimicrobial activities of compounds IIIa−d, V, VIa, VII were examined.

Preparation and alkylation reactions of 4-nitrobenzyl and 5-nitrofurfuryl sulfones

Substitution reaction of 5-nitrofurfuryl bromide (I) with sodium thiophenoxide and 4-chlorothiophenoxide in dimethyl sulfoxide at 20 °C and oxidation with dimethyl sulfoxide in the reaction medium afforded 5-nitrofurfuryl phenyl sulfone (IVa) and 5-nitrofurfuryl 4-chlorophenyl sulfone (IVb), respectively. Similarly, 4-nitrobenzyl bromide reacted with sodium 4-chlorothiophenoxide to give 4-nitrobenzyl 4-chlorophenyl sulfone (VII) and with sodium phenylsulfinate to afford 4-nitrobenzyl phenyl sulfone (IX). The sulfide intermediates were not isolated. The sulfone IX was used as substrate in alkylation reactions, catalysed by polyethylene glycols. Derivatives IVb and VII were identified by IR and mass spectroscopy, alkylation products by 1H NMR spectroscopy.

The metal complexes of amino acids and their N-substituted derivatives—VII. The i.r. spectra and normal coordinate analyses of bivalent metal complexes with N-methylglycine and N-phenylglycine

Twelve complexes of bivalent metals with N-methylglycine (sarcosine) and N-phenylglycine have been prepared over wide pH ranges and characterized by means of i.r. powder diffuse reflection, electronic spectra and magnetic susceptibility. These complexes are classified into two types, either with or without chloride ions, from elemental analyses: the former type (A) consists of ML 2· nH 2O (M = Co, Ni, Cu, Zn for L = sarcosinate anion; M = Co, Ni, Cu, Zn, Cd for L = N-phenylglycinate anion), which appear to be octahedral complexes. The metal is coordinated through a nitrogen atom, a carboxyl oxygen atom and water molecules or the carboxyl oxygen atoms of neighboring molecules. The latter type (B) consists of CoCl 2 (HL) 2·2H 2O, ZnCl 2 (HL) 2 and CdCl 2 (HL) (HL = sarcosine), in which the ligand has a zwitterion structure and has metal ions coordinated through only a carboxyl oxygen atom, but does not chelate through a nitrogen atom. In the cadmium (II) complex, a chloride ion seems to bridge to two cadmium (II) ions. In order to assign the observed frequencies of i.r. spectra in detail, normal coordinate analyses have been carried out for the complexes of the A type. The frequency separation of COO − antisymmetric and symmetric vibrations of A type complexes with sarcosine increases in the order: Co (II) < Ni (II) < Zn (II) < Cu (II). These separations of A type complexes with sarcosine and N-phenylglycine are larger than those of the corresponding complexes with glycine, alanine and other α-amino acids. The frequencies of metal-nitrogen and metal-oxygen stretching vibrations increase in the order: Co (II) < Zn (II) < Ni (II) < Cu (II) for sarcosine A type complexes.

Reaction of sulfene and dichloroketene with open‐chain N,N‐disubstituted α‐aminomethyleneketones. Synthesis of 4‐dialkylamino‐3,4‐dihydro‐6‐methyl‐5‐phenyl‐1,2‐oxathiin 2,2‐dioxides and of N,N‐disubstituted 4‐amino‐3‐chloro‐(6‐methyl‐5‐phenyl)(6‐benzyl)‐2H‐pyran‐2‐ones

AbstractCycloaddition of sulfene to N,N‐disubstituted 4‐amino‐3‐phenyl‐3‐buten‐2‐ones (III) occurred in good yield only in the case of aliphatic N‐substitution to give 4‐dialkylamino‐3,4‐dihydro‐6‐methyl‐5‐phenyl‐1,2‐oxathiin 2,2‐dioxides, whereas N,N‐disubstituted 4‐amino‐1‐phenyl‐3‐buten‐2‐ones (IV) did not react at all. Polar 1,4‐cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N‐substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N‐disubstituted 4‐amino‐3,3‐dichloro‐3,4‐dihydro‐(6‐methyl‐5‐phenyl)(6‐benzyl)‐2H‐pyran‐2‐ones, which were dehydrochlorinated with DBN to the corresponding 4‐amino‐3‐chloro‐(6‐methyl‐5‐phenyl)(6‐benzyl)‐2H‐pyran‐2‐ones (VII) in good yield. In some cases of aliphatic N,N‐disubstitution of III and IV, cycloaddition led directly to N,N‐dialkyl derivatives VII in low yield.

The metal complexes of heterocyclic β-diketones and their derivatives—VII. The synthesis, structure and i.r. spectral studies of 1-phenyl-3-methyl-4-trifluoroacetyl-pyrazolone-5 (HPMTFP) and its divalent metal complexes

The divalent metal complexes of Be, Mn, Co, Ni, Cu, Zn, Hg, Pb, and Mg with 1-phenyl-3-methyl-4-trifluoroacetyl-pyrazolone-5, (HPMTFP) have been prepared for the first time. The metal complexes were characterized by means of elemental analyses, conductivity measurements, proton NMR and i.r. spectroscopy, and it is concluded that the ligand, HPMTFP, reacts as a bidentate enol forming neutral metal chelates. The i.r. spectra were measured between 4000-200 cm −1 and assignments are proposed for the observed frequencies. Replacement of the methyl group by CF 3 group in the acetyl moiety of 1-phenyl-3-methyl-4-acetyl-pyrazolone-5, HPMAP, is found to increase the C ▪O and C ▪C bond strengths and decrease that of the MO bond. The magnitudes of MO stretching frequencies show good agreement with the Irving—Williams stability order Cu > Ni > Co > Mn > Zn.

Structure of reaction product of 3-aminocrotononitrile with esters of alkoxymethylenecyanoacetic acid

Study of dipole moments of 3,5-dicyanopyrridine derivatives II-IV has shown that cyclocondensation of 3-aminocrotononitrile with esters of alkoxymethylenecyanoacetic acid gives the2-pyridone derivative I which can be transformed in 2-chloro- or 2-bromo derivatives IV and V by action of the respective halogenation agents. The substance IV is conversed into 2-iodo- and 2-dimethylamino derivatives VI and VII on action of HI and dimethylformamide, respectively. Alkylation of the 2-pyridone I with methyl iodide takes place at nitrogen atom to give the compound IX. The 1,4-dihydropyridine derivative X has been obtained by action of NaBH4 on IV.

The vibrational spectra of germane and silane derivatives—VII. The infrared and Raman spectra of methylgermanium fluorides

The infrared and Raman spectra of the methylgermanium fluorides CH 3GeF 3, (CH 3) 2 GeF 2, and (CH 3) 3GeF have been recorded. The fundamental frequencies for each molecule were assigned and supported by normal coordinate analyses based on a modified valence force field. The torsional modes were not observed.