NEURAI NETWORKS IN Q. S. A. R STUDIES:Estimation and prediction of The anticonvuisant activities of thirty─eight cinnamamides

ltheory1.lprincipleoftheModifiedback-pr0pagation(MBP){'j1.2AIgorithmInthispapper.UsesM.B.PalgorithSupervisedLearn-ing.LeaningSignalC0nsists0ffeed-forwardandbackpropa-gati0n(Fig3).Alqorithm:lISigmoidfunctiony(x)=deIConnectionW',andQ,NInputtraimlngpattenSampleX,.andd:,,ftCalclate(coant)rea1ityValue0foatputY.VregulateWeightW,,W,,(l l)=W,,(l) V8.,01j-outputlayer:6'=y,(lwy,)(d,wy,)v.j-hiddenlayer:3j=O,(l-O,)=3kWjkkkisj(n l)layern0de.bN$O###At4oMBackto4StepContinuediterationuntilerr…     

神经网络用于苯乙胺衍生物的QSAR研究

将神经网络应用于定量构效关系（ＱＳＡＲ）中。采用改进的反向传播算法探讨了肾上腺素能阻断剂Ｎ，Ｎ－二甲基－２－溴苯乙胺取代衍生物的生物活性与取代基疏水参数（Σπ）和电子参数（Σσ）之间的关系。获得了精密的拟合及准确的预测（最大误差小于１０％），优于多无线性回归法。作为一种有效的化学计量学工具（Ｃｈｅｍｏｍｅｔｒｉｃｓ），神经网络具有良好的预测效果及较强的非线性处理功能，可望在ＱＳＡＲ及药物制剂中发挥重要作用。     

Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine.

A number of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and tested in vitro for anti-herpes and anti-human immunodeficiency virus (HIV) activity. Among these analogues, (R)-2'-methyl-PMEG [(R)-3] and 2',2'-dimethyl-PMEG (7) demonstrated potent anti-HIV activity in the XTT assay with EC50 values of 1.0 and 2.6 microM, respectively. The corresponding (S)-2'-methyl-PMEG [(S)-3] was found to be less potent against HIV. In addition, the (R) and (S) enantiomers of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine (HPMPG, 8) were prepared for comparison of biological activity, and shown to be active and equipotent against herpesviruses, but inactive against HIV.     

Morphiceptin analogs containing 2-aminocyclopentane carboxylic acid as a peptidomimetic for proline

As part of a program to study the structure-activity relationship of peptide opioids we report the synthesis, conformational characterization and biological activity of four analogs related to morphiceptin in which the proline at position two has been substituted with 2-aminocyclopentane carboxylic acid (βAc⁵c). The βAc⁵c residue is a beta amino acid with two chiral centers resulting in four possible configurations; two configurational cis (R,S and S,R) and two configurational trans (R,R and S,S) forms. Utilizing high resolution n.m.r. at 500 MHz and computer simulations with NOE restraints the chirality of the βAc⁵c residues are assigned. The analog containing the R,S-βAc⁵c is active at both the μ and δ-opioid receptors, with a slight preference for the μ-receptor. The (S,R), (S,S), and (R,R) analogs show minimal activity at the μ-receptor and are inactive at the δ-receptor. A comparison of the findings from the conformational analysis and biological assays lends insight into the structure-activity relationship of this important peptide opiate.     

The structure-inhibitory activity relationships study in a series of cyclooxygenase-2 inhibitors: a combined electronic-topological and neural networks approach

Structure-activity relationships study was performed for a few series of cyclooxygenase-2 (COX-2) inhibitors by using the Electronic-Topological Method combined with Neural Networks (ETM-NN). Specific molecular fragments were found for active compounds ('activity features') from both series by the ETM application. After this, a system of prognosis was developed as the result of training Kohonen's self-organizing maps (SOM) by the fragments. From the detailed analysis of all compounds under study, requirements necessary for a compound to be COX-2 inhibitor were formulated. The analysis showed that any requirements violation for a molecule resulted in a considerable decrease or even complete loss of its activity. The found activity features identified correctly different marketed drugs and new compounds that had passed pre-clinical and clinical trials; this fact confirms the workability of the system developed for the COX-2 inhibitory activity prediction.     

Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays

Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH(2), 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional (1)H NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent mu agonist which also displayed weak delta agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit mu antagonism have interaromatic distances of 7.0-7.9 A and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with delta opioid activity displayed an interaromatic distance of <7 A and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.     

咪唑四嗪酮类化合物对淋巴瘤细胞GM892A活性的构效关系研究

目的研究咪唑四嗪酮类化合物对淋巴瘤细胞GM892A活性的构效关系。方法采用量子化学和分子力学方法计算分子结构参数,利用正交变换和最佳变量子集回归法筛选建模变量,采用偏最小二乘法构建定量构效关系模型。结果得到一个较好的构效关系模型(R2=0.918,F=25.05,q2=0.788,press=0.820,P=0.000)。结论咪唑四嗪酮类化合物对淋巴瘤细胞GM892A的活性与取代基R1上净电荷Q1、摩尔折射率MR、水合能HE等结构参数相关。     

Prediction of enzyme activity with neural network models based on electronic and geometrical features of substrates

BackgroundArtificial Neural Networks (ANNs) are introduced as robust and versatile tools in quantitative structure-activity relationship (QSAR) modeling. Their application to the modeling of enzyme reactivity is discussed, along with methodological issues. Methods of input variable selection, optimization of network internal structure, data set division and model validation are discussed. The application of ANNs in the modeling of enzyme activity over the last 20 years is briefly recounted.MethodsThe discussed methodology is exemplified by the case of ethylbenzene dehydrogenase (EBDH). Intelligent Problem Solver and genetic algorithms are applied for input vector selection, whereas k-means clustering is used to partition the data into training and test cases.ResultsThe obtained models exhibit high correlation between the predicted and experimental values (R² > 0.9). Sensitivity analyses and study of the response curves are used as tools for the physicochemical interpretation of the models in terms of the EBDH reaction mechanism.ConclusionsNeural networks are shown to be a versatile tool for the construction of robust QSAR models that can be applied to a range of aspects important in drug design and the prediction of biological activity.     

DNA complexing antibiotics: daunomycin, adriamycin and their derivatives.

9-Acetyl-4-methoxy-7,8,9,11-tetrahydroxy-6,7,9,11-tetrahydroxy-o-(3'-amino-2',3',6'-trideoxy-alpha-L-lyxohexopyranoside) (daunomycin, daunorubicin, NSC-82 131, Daunoblasin), 14-hydroxy-daunorubicin (adriamycin, doxorubicin, NSC-123 127, Adriblastin), dihydrodaunomycin, their aglycones and other related compounds represent the group of S. peucetius derived antibiotics. The biosynthetic glycosides as well as some semisynthetic analogues or derivatives form strong complexes with double stranded DNA, which can be understood in terms of the known intercalation model. A clear relationship is found between the complex forming ability and the biological activity of the different compounds. The structure and configuration of the sugar moiety appear of primary importance for the stabilization of the complex and, therefore, for action. A class of side chain derivatives, namely adriamycin 14-0-esters, looks promising. Different tissue distribution of such derivatives may result in new useful anticancer drugs.     

S-2-pentyl-4-pentynoic hydroxamic acid and its metabolite s-2-pentyl-4-pentynoic acid in the NMRI-exencephaly-mouse model: pharmacokinetic profiles, teratogenic effects, and histone deacetylase inhibition abilities of further valproic acid hydroxamates and amides.

Structure-activity relationship studies of valproic acid (VPA) derivatives have revealed a quantitative correlation between histone deacetylase (HDAC) inhibition and induction of neural tube defects (NTDs) in the NMRI-exencephaly-mouse model, but this correlation has been, so far, limited to congeners with a carboxylic acid function. Whereas the classical HDAC inhibitor trichostatin A is active only as a hydroxamate but not as a carboxylic acid, we found that neither VPA amides nor hydroxamates inhibit HDACs, but can cause NTDs; e.g., 2-pentyl-4-pentynoic hydroxamic acid with its S-enantiomer being the potent teratogen. We therefore investigated the hypothesis that hydroxamic acid derivatives of VPA might be metabolized in vivo and may possibly be pro-teratogenic, as had been shown for valpromide but not valproic hydroxamic acid. We developed two stereoselective quantification methods based on chiral derivatization of VPA hydroxamates with (1R,2S,5R)-(-)-menthylchloroformate and carboxylic acid derivatives with (S)-(-)-1-naphthylethylamine, followed by gas chromatography-nitrogen phosphor detector analysis of biological samples. We then determined the pharmacokinetic profiles of S-2-pentyl-4-pentynoic hydroxamic acid and of S-2-pentyl-4-pentynoic acid in mice. S-2-Pentyl-4-pentynoic hydroxamic acid was found to be extensively metabolized to the corresponding carboxylic acid without affecting the stereochemistry at position C2. Furthermore, the metabolite S-2-pentyl-4-pentynoic acid was found to be very stable in vivo, with an extended half-life of 4.2 h compared with that of VPA, 1.4 h. Comparison of the individual HDAC inhibition abilities of additional VPA amides and hydroxamates, as measured by cellular and enzymatic assays, led us to the conclusion that both classes of VPA derivatives can be pro-teratogenic.     

Synthesis and biological activity of galactopyranoside derivatives of 4'-demethylepipodophyllotoxin showing VP-16 (etoposide)-like activity.

To investigate the role of the glucoside moiety in the biological activity of VP-16 (etoposide; 4'-demethylepipodophyllotoxin-ethylidene-beta-D-glucoside) and VM-26 (teniposide; 4'-demethyl-epipodophyllotoxin-thenylidene-beta-D-glucoside), a number of acetal and ketal derivatives of 4'-demethylepipodophyllotoxin (DMEP)-beta-D-galactoside were synthesized. The compounds synthesized included acetaldehyde, propionaldehyde, 2-thiophenecarboxaldehyde, phenylacetaldehyde and acetone derivatives. In contrast to the glucose derivatives, where the acetal ring is trans to the pyranose ring, in galactose derivatives it is located in the cis position. The activities of the above compounds have been measured in two different biological assays, based on cross resistance towards mutants exhibiting specific resistance to VP-16/VM-26-like drugs and DNA-strand breaks as measured by the alkaline elution technique. All of the above compounds showed specific cross resistance to VpmR mutants (mutants resistant to VP-16 and VM-26) and caused a dose-dependent enhancement in DNA-strand breakage, providing evidence that they possessed the same kind of biological activity as VP-16 and VM-26. The relative activities of the DMEP-galactose derivatives have been compared with the corresponding DMEP-glucoside compounds. These studies reveal that, for the acetal and ketal derivatives with small R groups (acetaldehyde and acetone derivatives), the activities in the two series are comparable. However, for derivatives with larger, more hydrophobic R groups (2-thiophene or phenylacetaldehyde), the glucoside derivatives showed about 8-10-fold higher activity in comparison with the corresponding galactoside compounds.     

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.     

Discovery of novel trisubstituted asymmetric derivatives of (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner

In our structure-activity relationship study on 3,6-disubstituted pyran derivatives, we have carried out asymmetric synthesis and biological characterization of trisubstituted (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol and (3S,4R,6S)-6-benzhydryl-4-benzylaminotetrahydropyran-3-ol derivatives and their enantiomers. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]-5-HT, and [(3)H]NE, respectively. Compounds were also tested for their binding affinity at the DAT by their inhibition of [(3)H]WIN 35,428. Biological results indicated that regioselectivity and stereoselectivity played important roles in determining activity for monoamine transporters as only (-)-isomers of 2-benzhydryl-5-benzylaminotetrahydropyran-4-ol derivatives exhibited appreciable potency for the monoamine transporters, in particular for the SERT and NET. Among the active analogues, (-)-9d exhibited potent and selective affinity at the NET (K(i), [(3)H]NE = 4.92 nM; DAT/NET = 91 and SERT/NET = 140). One of the derivatives with p-methoxybenzyl substitution, (-)-9a, was potent at both SERT and NET (K(i), [(3)H]-5-HT = 25.9 and [(3)H]NE = 15.8 nM, respectively). In the active analogue series ((-)-9a-(-)-9e), a cis-relationship between the biphenyl and the amino moiety was maintained for the SERT and NET interactions, as was observed with our earlier 3,6-disubstituted pyran compounds for the DAT interaction. To the best of our knowledge, this current series of compounds represents a novel class of pyran derivatives as blockers for monoamine transporters.     

Application of Artificial Neural Networks to Eating Disorders

An experimental application of Artificial Neural Networks to Eating Disorders is presented. The sample, composed of 172 cases (all women) collected at the Centre for the Diagnosis and Treatment of Eating Disorders of the 1st Medical Division of the St. Eugenio Hospital of Rome, was subdivided, on the basis of the diagnosis made by the specialist of the St. Eugenio, into four classes: Anorexia Nervosa (AN), Nervous Bulimia (NB), Binge Eating Disorders (BED) and Psychogenic Eating Disorders that are Not Otherwise Specified (PED-NOS). The data base was composed of 124 different variables: generic information, alimentary behavior, eventual treatment and hospitalization, substance use, menstrual cycles, weight and height, hematochemical and instrumental examinations, psychodiagnostic tests, etc. The goal of this experiment was to verify the accuracy of the Neural Networks in recognising anorexic and bulimic patients. This article describes 6 experiments, using a Feed Forward Neural Network, each one using different variables. Starting from only the generic variables (life styles, family environment, etc.) and hematoclinical and instrumental examinations, a Neural Networks provided 86.94% of the prediction precision. This work is meant to be a first contribution to creating diagnostic procedures for Eating Disorders, that would be simple and easy-to-use by professionals who are neither psychologists nor psychiatrists nor psychotherapists but who are, however, among the first to meet these patients and who are therefore called upon to give such patients the very first pieces of advice on seeking proper treatment.     

Synthesis and antiviral activity of 9-alkoxypurines. 2. 9-(2,3-Dihydroxypropoxy)-, 9-(3,4-dihydroxybutoxy)-, and 9-(1,4-dihydroxybut-2-oxy)purines.

Reaction of alkenoxyamines (3,5) or (R,S)-, (R)-, and (S)-hydroxy-protected derivatives of hydroxyalkoxyamines (20a,b, 37a-c) with 4,6-dichloro-2,5-diformamidopyrimidine (4) and cyclization of the resultant 6-[(alkenoxy)amino]-and 6-(alkoxyamino)pyrimidines (6,7,21a,b, 38a,b,c) by heating with diethoxymethyl acetate afforded 9-alkenoxy- and 9-alkoxy-6-chloropurines (9,10,22a,b, 39a-c, 40a). These were subsequently converted to 9-(2,3-dihydroxypropoxy), 9-(3,4-dihydroxybutoxy), and 9-(1,4-dihydroxybut-2-oxy) derivatives of guanine and 2-aminopurine (13-16, 25-28, 41a-c, 42a). A 2-amino-6-methoxypurine derivative (17) was also prepared. The racemic guanine derivative 13 showed potent and selective activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), but was less active against varicella zoster virus (VZV). Its antiviral activity is attributable to the S isomer (28), which was found to be more active than acyclovir against HSV-1 and HSV-2 and about 4 times less active than acyclovir against VZV. The S enantiomer of 9-(1,4-dihydroxybut-2-oxy)guanine (41c) also showed noteworthy antiviral activity in cell culture. Although this acyclonucleoside (41c) is only weakly active against HSV-1 and inactive against HSV-2, it is about twice as active as acyclovir against VZV.     

Oxindole derivatives as orally active potent growth hormone secretagogues.

A series of substituted oxindole derivatives was synthesized and evaluated for growth hormone (GH) releasing activity using cultured rat pituitary cells. (+)-6-Carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity (EC(50) = 3.0 nM), while the other enantiomer 37R had reduced activity. The absolute configuration of 37S was confirmed by X-ray crystallographic analysis. Compound 37S showed a good pharmacokinetic profile in rats with 28% oral bioavailability at 10 mg/kg and excellent in vivo activity as evidenced by a significant weight gain after 4 days of oral administration at 10 mg/kg twice a day. Compound 37S displaced the binding of (35)S-MK-677 to human GHS-R with an IC(50) value of 1.2 +/- 0.2 nM.     

Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

神经网络用于环丙胺类衍生物的构效关系研究

将神经网络应用于定量构效关系研究。用改进的反传算法探讨了单胺氧化酶抑制剂N-(苯氧乙基)环丙胺取代衍生物的生物活性与取代基电子效应σ、疏水作用π、空间效应Es等参数之间的定量关系。给出了精密拟合和准确预测(最大误差均小于10%),优于经典的多元线性回归及逐步回归方法。作为一种有效的计量化学新方法,神经网络有良好的预测能力和非线性处理功能,从而可望在QSAR研究中发挥重要作用。     

Synthesis and antibacterial activity of C-2 alkenylthio-carbapenem derivatives

A number of C-2 aminoalkenylthio-carbapenem derivatives possessing both the (5R,6R, 8S)- and the (5R,6S,8R)-stereochemistries have been prepared from the olivanic acids MM 22382 and MM 22383, respectively. Certain members of this new class of compounds displayed potent, broad spectrum antibacterial activity as well as improved stability to human kidney homogenate.     

(R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid (CV-5975): a new potent and long-lasting inhibitor of angiotensin converting enzyme

The synthetic design and the biological activities of structurally new angiotensin converting enzyme (ACE) inhibitors, (R)-3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid derivatives, are described. A number of compounds in this series showed potent ACE inhibitory activity in vitro and in vivo. Structure-activity studies indicated that a piperidyl moiety on the amino group at the 3-position in this series conferred long-lasting ACE inhibitory activity and that the duration of activity depended on the length of the carbon chain in the 1-carboxy-omega-(4-piperidyl)alkyl group. (R)-3-[(S)-1-carboxy-5-(4-piperidyl)-pentyl]amino-4-oxo-2,3,4,5-tetrahydro- 1,5-benzothiazepine-5-acetic acid (CV-5975) was selected as the most promising ACE inhibitor for further studies because of its marked inhibitory activity.