Quantitative Structure–Activity Relationship Study of 5-Iodo- and Diaryl-analogues of Tubercidin: Inhibitors of Adenosine Kinase

The adenosine kinase inhibitory (AKI) activity of 5-iodo and diaryl analogues of tubercidin is quantitatively analyzed using Fujita-Ban and Hansch type analyses. The Fujita-Ban analysis being a non-parametric approach assigned the highest contribution to Cl at the X-position, C6H4-4-Cl, C6H5, 2-furanyl and I at the Y-position and CH2NH2 and CH3 at the Z-position. In addition, a OH substituent at the C-position also emerged as a better choice possibly due to its engagement in hydrogen bonding with some active site function. Thus a compound having Cl, C6H4-4-Cl, CH2NH2 and OH respectively at X-, Y-, Z- and C-positions is predicted to have a potency nearly 1.5 orders of magnitude higher than the most potent compound of the parent data set. The Hansch type analysis, on the other hand, is a parametric approach and is carried out on two sub-sets of original compounds. This sub-division is based on size and nature of the substituents present at the X- and Y-positions. For the compounds in the first sub-set the derived significant correlation equation suggested that the substituent at the Y-position exhibiting a higher field effect and a substituent such as Cl and CH2NH2 at X- and Z-positions, respectively, are important for a compound to show increased AKI activity. Thio/alkylthio at X and CH2OCH3 at Z, on the other hand, lead to a detrimental effect. Similarly for the compounds in the second sub-set, the derived significant correlation equation showed that a substituent at the X-position having a higher negative field effect, a substituent at the Y-position having bulky groups and the C-position occupied by a OH group are essential for enhancement of the activity of a compound.     

Quantitative structure-activity relationship study of benzylsulfanyl imidazoles as cytokine release inhibitors

Benzylsulfanyl imidazole derivatives (Figure 1) have shown their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells or human whole blood. Such anticytokine actions of these congeners are quantitatively studied using Fujita-Ban and Hansch type analyses. The Fujita-Ban study resulted in the contributions of different substituents and the parent moiety for the inhibitions of cytokines TNF-alpha and IL-1beta. The substituents that have a higher positive contribution to the given activity, relative to substituents of the parent moiety at different positions were then used to obtain a trend for the active analogues. None of the substituents present at X, Y, 2-R and 3-R, appears to be advantageous over the substituents of the parent moiety for inhibition of both the cytokines. However, the substituents at 4-R, 5-R and 6-R help to improve the inhibitory actions of the compounds for both cytokines. The optimal activities seem to be manifested by compounds in which 4-R, 5-R and 6-R are substituted respectively by OH (or SOCH3 and SO2CH3), Cl and OH for inhibition of TNF-alpha, whereas by SOCH3 (or SO2CH3 and OH), H and OH for inhibition of IL-1beta. The Hansch type analysis, on the other hand, revealed that the F-substituents of the X-position and a less bulky structural moiety such as--S(CH2)2--at the Y-incision are advantageous in improving the inhibitory action towards TNF-alpha. Similarly, a less bulky/polar substituent present at 2-R and not having a hydrogen-bond donor property, while a more hydrophobic substituent at 3-R and hydrogen-bond acceptor substituent at 4-R are helpful in augmenting inhibitory activity of a compound. However, for inhibition of cytokine IL-1beta, it emerged that the X-substituents that transmits a higher negative resonance effect, the Y-substituent that offers less molecular bulk are beneficial. The R-substituents, being more electron donors at the meta-position, less hydrophobic at the para-position and offering smaller refractivity (less bulky and or polar) at the ortho-position are likewise helpful in improving the activity of a compound.     

Quantitative structure-activity relationship study of novel rhinacanthins and related naphthoquinone esters as anticancer agents

The anticancer activity of rhinacanthins and related naphthoquinone esters is quantitatively analyzed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that naphthalene ring instead of benzene ring, dimethyl substitution at R(1) and R(2), and hydrogen-bond acceptor substituents at R(3) (Figure 1) are advantageous to improve the activity of a compound against KB cell lines. This in turn leads to the suggestion that the rhinacanthin-N scaffold is the structural entity that needs exploration for new potential compounds. Further, in the Fujita-Ban analysis, it is observed that the compounds bearing a OMe substitution, relative to H, at R(4) have a slight positive contribution to pIC(50) (KB) whereas the substituents H or OMe at R(5), relative to OH, have negative contributions. In conformity with these findings, the Hansch approach revealed that a more hydrophobic group at R(4) and a more hydrophilic group at R(5) positions are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection to design more potent compounds of the series.     

Quantitative structure-activity relationship study on N-(pyridin-4-yl)-(indol-3-yl) alkylamides as antiallergic agents

The antihistamine activity of N-(pyridin-4-yl)-(indol-3-yl) alkylamides has been analyzed using Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the antiallergic actions of these analogues. From both approaches it is revealed that the small size substituents at R and R2 and non-hydrogen bond acceptor substituent at R improve histamine antagonist activity of a compound. Likewise, a small incision such as -CH2CONH-serving as the spacer between pyridinyl and indolyl rings and a bigger substituent like 4-FBn at R1 are also desirable for inhibitory activity.     

Quantitative structure-activity relationship study of new potent and selective antagonists at the 5-HT(1A) and adrenergic alpha(1d) receptors: Derivatives of spiroethyl phenyl(substituted)piperazine

The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT(1A) and adrenergic alpha(1d) receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT(1A) receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pK(i) values 10.57 and 10.12 respectively. For the adrenergic alpha(1d) receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series.     

Probing the physicochemical and structural requirements for glycogen synthase kinase-3alpha inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides

Glycogen synthase kinase-3alpha (GSK-3alpha) was recently found to be an attractive target for the treatment of Alzheimer's disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3alpha binding. Using Fujita-Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3alpha inhibition.     

Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity

A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl (MeSO(2)) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO(2)NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure-activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1-39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC(50)>100 microM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.     

Interaction of uridine diphosphate glucose analogs with calf liver uridine diphosphate glucose dehydrogenase. Influence of substituents at C-5 of pyrimidine nucleus.

The interaction of alpha-D-glucopyranosyl pyrophosphates of 5-X-uridines (X = CH3, NH2, CH3O, I, Br, Cl, OH) with uridine diphosphate glucose (UDPGlc) dehydrogenase (EC 1.1.1.22) from calf liver has been studied. All the derivatives investigated were able to serve as substrates for the enzyme. The apparent Michaelis constants for UDPGlc-analogs were dependent both on electronic and steric factors. Increase of substituent negative inductive effect lead to decrease of pKa for ionization of the NH-group in the uracil nucleus and, consequently, to a diminishing of the proportion of the active analog species under the conditions of assay. After correction for the ionization effect, the Km values were found to depend on the van der Waals radius of the substituent. The value of 1.95 A seems to be critical, as the analogs with bulkier substituents at C-5 showed a decreased affinity to the enzyme. The maximal velocity values of the analogs were also dependent on nature of the substituent. Good linear correlation between log V and substituent hydrophobic phi-constant was observed for a number of the analogs, although V values for the nucleotides with X = H, OH or NH2 were higher than would be expected on the basis of the correlation. The significance of the results for understanding of the topography of UDPGlc dehydrogenase active site is discussed.     

Interaction of the antitumor agents cis,cis,trans-PtIV(NH3)2Cl2(OH)2 and cis,cis,trans-PtIV[(CH3)2CHNH2]2Cl2(OH)2 and their reduction products with PM2 DNA

The ability of two platinum(IV) antitumor agents, cis,cis,trans-PtIV[(CH3)2CHNH2]2Cl2(OH)2 (2) and cis,cis,trans-PtIV(NH3)2Cl2(OH)2 (4), to interact with PM2 DNA was examined. Analysis using gel electrophoresis showed that neither compound is able to alter the electrophoretic mobilities of the three forms of PM2 DNA in the gel. However, incubation of 2 and 4 with 2 equiv of Fe(ClO4)2 X 6H2O or 1 equiv of ascorbic acid results in reduction to yield the divalent complexes cis-PtII(NH3)2Cl2 (1) and cis-PtII-[(CH3)2CHNH2]2Cl2 (3). The structures of the reduction products were characterized by using elemental analysis as well as infrared and 195Pt NMR spectroscopies. Both 1 and 3 were found to bind to and unwind supercoiled form I PM2 DNA. The aforementioned observations support the suggestion that reduction is a means of activating the antitumor properties of 2 and 4.     

N,N-bis(2-mercaptoethyl)methylamine: a new coligand for Tc-99m labeling of hydrazinonicotinamide peptides

Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with Tc(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries. Tridentate ligands, such as bis(mercaptoethyl)methylamine (NS2), may constrain the possible coordination geometries and improve overall stability. To investigate this, we synthesized NS2, converted the [Tc-mannitol-For-MLFK-HYNIC] to the corresponding NS2-containing complex [Tc-NS2-For-MLFK-HYNIC], and compared its infection imaging and biodistribution properties with [Tc-mannitol-For-MLFK-HYNIC]. Conversion to the NS2 complex was confirmed by HPLC which showed a single unique hydrophobic species with retention time greater than the [Tc-mannitol-For-MLFK-HYNIC] complex. Imaging experiments with both preparations were performed in rabbits with E. coli infections in the left thigh. Tissue radioactivity measurements demonstrated that compared to Tc-mannitol-peptide, accumulation of Tc-NS2-peptide was lower in blood, heart, and normal muscle and higher in spleen, infected muscle, and pus (p < 0.01). These results indicate that the Tc-NS2-peptide complex is chemically more homogeneous and exhibits improved infection localization and biodistribution properties. In an effort to model the interactions of the metal-HYNIC core with NS2 and related ligand types, the reactions of [ReCl3(NNC5H4NH)(NHNC5H4N)] and [99TcCl3(NNC5H4NH)(NHNC5H4N)], effective structural analogues for the [M(NNC5H4NH(x))2] core, with NS2, C5H3N-2,6-(CH2SH)2, O(CH2CH2SH)2, and S(CH2CH2SH)2 were investigated and the compounds [M[CH3N(CH2CH2S)2](NNC5H4N)(NHNC5H4N] (M = 99Tc (5a), Re (5b)), [Re[C5H3N-2,6-(CH2S)2](NNC5H4N)(NHNC5H4N)].CH2Cl2.0.5MeOH (7), [Re[SCH2CH2)2O] (NNC5H4N)(NHNC5H4N)] (8), and [Re[(SCH2CH2)2S](NNC5H4NH)(NHNC5H4N)]Cl (9) were isolated. Similarly, the reaction of [ReCl3(NNC5H4NH)(NHNC5H4N)] with the bidentate ligands pyridine-2-methanethiol and 3-(trimethlysilyl)pyridine-2-thiol led to the isolation of [ReCl(C5H4N-2-CH2S) (NNC5H4N)(NHNC5H4N)] (10) and [Re(2-SC5H3N-3-SiMe3)2 (NNC5H4N)(NHNC5H4N)] (11), respectively, while reaction with N-methylimidazole-2-thiol yielded the binuclear complex [Re(OH)Cl(SC3H2N2CH3)2(NNC5H4N)2 (NHNC5H4N)2] (12). The analogous metal-(HYNIC-OH) precursor, [ReCl3[NNC5H3NH(CO2R)] [NHNC5H3N(CO2R)]] (R = H, 13a; R = CH3, 13b) has been prepared and coupled to lysine to provide [RCl3[NNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)] [NHNC5H3NH(CONHCH2CH2CH2CH2CH(NH2)CO2H)]].2HCl (14.2HCl), while the reaction of the methyl ester 13b with 2-mercaptopyridine yields [Re(2-SC5H4N)2[NNC5H3N(CO2Me)][NHNC5H3N(CO2Me)]] (15). While the chemical studies confirm the robustness of the M-HYNIC core (M = Tc, Re) and its persistence in ligand substitution reactions at adjacent coordination sites of the metal, the isolation of oligomeric structures and the insolubility of the peptide conjugates of 13, 14, and 15 underscore the difficulty of characterizing these materials on the macroscopic scale, an observation relevant to the persistent concerns with reagent purity and identity on the tracer level.     

Studies on activities, cell up take and DNA binding of four multinuclear complexes of the form: [[trans-PtCl(NH(3))(2)](2)mu-[trans-Pd(NH(3))(2)-(H(2)N(CH(2))(n)NH(2))(2)]]Cl(4) where n=4-7

The activity against human cancer cell lines including ovarian: A2780, A2780(cisR), cell up take, DNA-binding and nature of interaction with pBR322 plasmid DNA have been studied for four multinuclear complexes code named DH4Cl, DH5Cl, DH6Cl and DH7Cl, having the general formula: [[trans-PtCl(NH(3))(2)](2)mu-[trans-Pd(NH(3))(2)-(H(2)N(CH(2))(n)NH(2))(2)]]Cl(4) where n=4, 5, 6 and 7 for DH4Cl, DH5Cl, DH6Cl and DH7Cl, respectively. The compounds are found to exhibit significant anticancer activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R). DH6Cl in which the linking diamine has six carbon atoms is found to be the most active compound. As the number of carbon atoms in the linking diamine is decreased below six and increased above six, the activity is found to decrease, illustrating structure-activity relationship. All the multinuclear compounds are believed to form a plethora of long-range interstrand GG adducts with DNA dictated by the sequence of bases in the DNA strands. Increasing prevention of BamH1 digestion with the increase in concentration of the compounds is due to global changes in DNA conformation brought about by interstrand long-range binding of the compounds with DNA.     

Acetylcholinesterase inhibition by diaza- and dioxophosphole compounds: synthesis and determination of IC50 values

Cholinesterases are targets for organophosphorus compounds which are used as pesticides, insecticides, chemical warfare agents and drugs for the treatment of disease such as glaucoma or parasitic infections. Most organophosphorus compounds impart their toxic action via inhibition of cholinesterases by reacting at an essential serine hydroxyl group. The inhibition process depends on the leaving group, stereochemistry and reactivity of the organophosphorus compound. In this study, the inhibitory potency of two isoelectronic and isostructural diaza- and dioxophospholes A (CH3C6H3 O2P(O)Cl) and B (CH3C6H3(NH)2P(O)Cl) against human acetylcholinesterase (hAChE) was examined by spectrophotometric measurements based on Ellman's method. Results indicated that compounds A and B were irreversible inhibitors with IC50 values of 0.48 and 1.54mM, respectively and inactivation constants (k(i)) of 0.0363 and 0.0207min(-1), respectively. The differences in the inhibitory potency of two phosphole compounds is discussed with respect to their structures. In addition, the synthesis and characterization of compound A is discussed.     

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.     

Effects of polyamines and analogs on staphylococcal nuclease.

The promoting activity of polyamine analogs (IV approximately XV) on staphylococcal nuclease with DNA as the substrate was compared with that of natural polyamines (I APPROXIMATELY III): I. NH2(CH2)3NH(CH2)4NH(CH2)3NH2(spermine); II. NH2(CH2)3NH(CH2)3NH(CH2)3NH2(thermine); III. NH2(CH2)4NH2 (putrescine); IV. CN(CH2)2NH(CH2)4NH(CH2)2CN; V. HOOC(CH2)2NH(CH2)4NH(CH2)2COOH; VI. C2H5OOC(CH2)2NH(CH2)4NH(CH2)2COOC2H5; VII. HO(CH2)3NH(CH2)4HH(CH2)3OH; VIII. CH3COHH(CH2)3NH(CH2)4NH(CH2)3NHCOCH3; IX. C2H5NH(CH2)3NH(CH2)4NH(CH2)3NHC2H5; X. NH2(CH2)3S(CH2)4S(CH2)3NH2; XI. NH2(CH2)3NH(CH2)2O(CH2)2NH(CH2)3NH2; XII. NH2(CH2)3NCH3(CH2)4HCH3(CH2)3NH2; XIII. CN(CH2)2NCH3(CH2)4NCH3(CH2)2CN; XIV. (CH3)2N(CH2)3NCH3(CH2)4NCH3(CH2)3N(CH3)2; XV. NH2(CH2)2O(CH2)2NH2 Replacement of the terminal groups by CN, COOH, COOEt, NHAc, NHEt, or N(CH3)2 remarkably decreased the activity. The compound VII with terminal hydroxyl groups had a lower promoting activity at low concentrations, but revealed higher activity at higher concentrations and, in contrast to spermine, no inhibition at all even at very high concentrations. Replacement of both internal amino groups by sulfur or NCH3 decreased the activity. The introduction of an ether bond into the internal methylene groups (compound XI) highly decreased the activity. Based upon these findings the possible relationship between structure and activity is discussed.