Isoenzyme- and Allozyme-Specific Inhibitors: 2,20-Dihydroxybenzophenones and Their Carbonyl N-Analogues that Discriminate between Human Glutathione Transferase A1-1 and P1-1 Allozymes

The selectivity of certain benzophenones and their carbonyl N-analogues was investigated towards the human GSTP1-1 allozymes A, B and C involved in MDR. The allozymes were purified from extracts derived from E. coli harbouring the plasmids pEXP5-CT/TOPO-TAhGSTP1* A, pOXO4-hGSTP1*B or pOXO4-hGSTP1*C. Compound screening with each allozyme activity indicated three compounds with appreciable inhibitory potencies, 12 and 13 with P1-1A 62% and 67%, 11 and 12 with P1-1C 51% and 70%, whereas that of 15 fell behind with P1-1B (41%). These findings were confirmed by IC50 values (74–125 lM). Enzyme inhibition kinetics, aided by molecular modelling and docking, revealed that there is competition with the substrate CDNB for the same binding site on the allozyme (Ki(13/ A) = 63.6 +- 3.0 lM, K (15/B) = 198.6 +- 14.3 lM, and Ki(11/ C) = 16.5 +- 2.7 lM). These data were brought into context by an in silico structural comparative analysis of the targeted proteins. Although the screened compounds showed moderate inhibitory potency against hGSTP1-1, remarkably, some of them demonstrated absolute isoenzyme and/or allozyme selectivity

Designer Xanthone An Inhibitor Scaffold for MDR-Involved Human Glutathione Transferase Isoenzyme A1-1

Glutathione transferases (GSTs) are cell detoxifiers involved in multiple drug resistance (MDR), hampering the effectiveness of certain anticancer drugs. To our knowledge, this is the first report on well-defined synthetic xanthones as GST inhibitors. Screening 18 xanthones revealed three derivatives bearing a bromomethyl and a methyl group (7) or two bromomethyl groups (8) or an aldehyde group (17), with high inhibition potency (>85%), manifested by low IC50 values (7: 1.59 ± 0.25 μM, 8: 5.30 ± 0.30 μM, and 17: 8.56 ± 0.14 μM) and a competitive modality of inhibition versus CDNB (Ki(7) = 0.76 ± 0.18 and Ki(17) = 1.69 ± 0.08 μM). Of them, derivative 17 readily inhibited hGSTA1-1 in colon cancer cell lysate (IC50 = 10.54 ± 2.41 μM). Furthermore, all three derivatives were cytotoxic to Caco-2 intact cells, with 17 being the least cytotoxic (LC50 = 151.3 ± 16.3 μM). The xanthone scaffold may be regarded as a pharmacophore for hGSTA1-1 and the three derivatives, especially 17, as potent precursors for the synthesis of new inhibitors and conjugate prodrugs for human GSTs

2,20-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1

The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18 ± 0.02 to 1.77 ± 0.10 μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4 ± 0.4 μM and 87 ± 1.9 μM, respectively), in addition to the strong enzyme inhibition profile (IC50(6) = 1,77 ± 0.10 μM; IC50(14) = 0.33 ± 0.05 μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs

A convenient access to benzo-substituted phthalazines as potential precursors to DNA intercalators

2-Nitro-5-methoxybenzaldehyde is converted to amines 2 and 7 via two alternative routes. Upon diazotisation and Sandmeyer reaction, halides 4 and 9 are formed, which, through lithiation and formylation lead to the o-phthalaldehyde. Further cyclisation with hydrazine gives the 5-methoxy-substituted phthalazine. (C) 2001 Elsevier Science Ltd. All rights reserved

A mild procedure for the production of secondary amines from oximes and benzisoxazoles

-2-Hydroxybenzaldoximes are reduced under mild conditions of ammonium formate/Pd-C in methanol to give secondary amines. Benzisoxazoles react under the same mild conditions to give the same products. A possible mechanism is suggested, involving the intermediacy of the benzisoxazole in the oxime conversion. (C) 2003 Elsevier Ltd. All rights reserved

Intramolecular cyclization of β-nitroso-o-quinone methides : A theoretical endoscopy of a potentially useful innate 'reclusive' reaction

Date of Acceptance: 06/11/2014Oxidatively generated β-nitroso-o-quinone methides undergo an o- and/or peri-intramolecular cyclization to arene-fused 1,2-oxazoles, 1,2-oxazines or indoles. The reaction, found to be an innate process, has been scrutinized by DFT/B3LYP and MP2 calculations. Due to its rapidity, the process has been termed a 'reclusive' one. Competing o-(1,5)- and peri-(1,6)- or (1,5)-cyclizations advance via successive transition states. Activation barriers are drastically lowered in AcOH, probably through H hopping or tunnelling whereas they are barely reduced in other solvents. Aromaticity indices, such as HOMA, IA and ABO, have been used to assess the stability of the end-heterocycles and the preponderance of any one of them. Thus, the preferred cyclization mode, that is, the prevalence or exclusive formation of one of the heterocycles, appears to be oxidant-directed rather than determined by the quinone methide geometry. The question of the peri-cyclization, being a primary or a secondary process, has been tackled.Peer reviewe

Cerium(IV) ammonium nitrate for the tandem nitration and oxidative rearrangement of 2-acetyl-1-naphthol benzoylhydrazones into 1,2-diacylnaphthalenes; synthesis of benzo[f]phthalazines

A novel nitration and oxidation reaction sequence of 2-Acetyl-1-naphthol benzoylhydrazones with CAN is presented. There is strong indication that nitration precedes an oxidative rearrangement to 1,2-diacyl-4- nitronaphthalenes or oxidative electrocyclisation to 3-methyl-5-nitronaphtho[2,1-d]isoxazole. Condensation of 1,2-diacyl-4-nitronaphthalenes with hydrazine hydrate yields 1,4-disubstituted benzo[f]phthalazines.status: publishe

Novel thermal and microwave-assisted facile route to naphthalen-2(1H)-ones via an oxidative alkoxylation-ring-opening protocol

Several novel 1,1-disubstituted-8-hydroxynaphthalen-2(1H)-ones have been efficiently synthesized via a two-step sequence from 2-hydroxy-1-naphthaldehyde oxime. The methodology involves oxidative ring closure and alkoxylation to 3a-alkoxynaphtho[1,8-de][1,2]oxazin-4(3aH)-ones, followed by thermal ring-opening. Both thermal and microwave irradiation conditions were used. A novel one-pot reaction of oxime to 8-isopropoxynaphthalene-1,7-diol using microwave irradiation is also reported

Arene-fused 1,2-oxazole N-oxides and derivatives. The impact of the N-O dipole and substitution on their aromatic character and reactivity profile. Can it be a useful structure in synthesis? A theoretical insight

DFT calculations have shown that the N-O dipole of benzene- and naphthalene-fused 1,2-oxazole N-oxides causes a distortion of their σ and π frame, concentrated on the 1,2-oxazole ring, such that it increases its susceptibility to opening. The distortion forces the benzene ring into some diene geometry, thus, reducing π delocalization over the bi- or tricyclic structure and ultimately their aromatic character. C-3 substitution has a marked influence mainly on the naphthalene-fused N-oxides. C-5 and particularly C-6 substitution, as the position of most extended interaction with the N-O dipole through the π ring density, contribute to the distortion of the 1,2-oxazole geometry and thereby to the decrease of aromaticity of the structure. Bond uniformity (IA), average bond order (ABO) and Harmonic Oscillator Model of Aromaticity (HOMA) indices have been recruited to measure aromaticity changes. IA and ABO appear to be more credible to 1,2-benzoxazole N-oxides and 1,2-naphthoxazole N-oxides, respectively, while HOMA has been found equally reliable to both. Hardness and dipole moments follow similar trends. Energies, localization and separation of the four frontiers orbitals, i.e. HO, HO-1, and LU, LU+1, indicate a rather notable aromatic character of the N-oxides. Their reactivity profile, portrayed by descriptors such as Fukui and electro(nucleo)philicity Parr functions, shows good agreement with experimental outcomes towards electrophiles but succumbs to discrepancies towards nucleophiles due to the susceptibility of the hetero-ring to opening. The "push-pull" character of the N-O dipole and more importantly the extent of its double bonding direct site selectivity.Peer reviewe