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Biomedical subjects

Maurizio Botta

Publications and source records attributed to Maurizio Botta.

At least 55 records · Page 3Linked to original sources
PubMed2003

New pyrimido[5,4-b]indoles as ligands for alpha(1)-adrenoceptor subtypes.

A new series of compounds were designed as structural analogues of the alpha(1)-AR ligand RN5 (4), characterized by a tricyclic 5H-pyrimido[5,4-b]indole-(1H,3H)2,4-dione system connected through an alkyl chain to a phenylpiperazine (PP) moiety. These compounds were synthesized and tested in binding assays on human alpha(1A)-AR, alpha(1B)-AR, and alpha(1D)-AR subtypes expressed in HEK293 cells. Several structural modifications were performed on the PP moiety, the tricyclic system, and the connecting alkyl chain. Many of the new molecules showed a preferential affinity for the alpha(1D)-AR subtype. Some compounds, including 39 and 40, displayed substantial alpha(1D)-AR selectivity with respect to alpha(1A)-AR, alpha(1B)-AR, serotonergic 5-HT(1A), 5-HT(1B), 5-HT(2A), and dopaminergic D(1) and D(2) receptors. Two conformationally rigid analogues of 4, useful for studying the architecture of the receptor/ligand complex, were also prepared and tested. A subset of the new compounds was then used to evolve a preliminary pharmacophore model for alpha(1D)-AR antagonists, based on a more generalized model we had developed for alpha(1)-AR antagonists. This new model rationalized the relationships between structural properties and biological data of the pyrimido[5,4-b]indole compounds, as well as other compounds.

Adrenergic alpha-Antagonists↗
PubMed2003

Research on L-nucleosides. Synthesis and biological evaluation of a series of L- and D-2',3'-dideoxy-3'-[tris(methylthio)methyl]-beta-pentofuranosyl nucleosides.

Novel nucleoside analogues of both D and L enantiomeric series were prepared by coupling reaction between a 2',3'-dideoxy-3'-modified furanose moiety and four different nucleobases. Though in all cases anomeric mixtures of nucleosides were obtained, the presence of the sterically bulky 3'-tris(methylthio)methyl group allowed a good stereoselectivity level. All the compounds of both enantiomeric series showed high IC(50) values as HSV-1 TK inhibitors and scarce ability to be phosphorylated by HSV-1 TK. In order to overcome possible problems related to the first phosphorylation step and to facilitate the penetration of the molecule through the cellular membrane, a monophosphate prodrug containing a long lipophilic chain was synthesized. No appreciable antiviral activity was exhibited by this molecule.

3T3 Cells↗
PubMed2003

alpha1-Adrenoceptor antagonists. 5. Pyridazinone-arylpiperazines. Probing the influence on affinity and selectivity of both ortho-alkoxy groups at the arylpiperazine moiety and cyclic substituents at the pyridazinone nucleus.

Our previous work on pyridazinone-arylpiperazine derivatives suggested some structural features that a compound should have to show high affinity and good selectivity for alpha(1) adrenoceptors (AR) with respect to alpha(2)-AR. Accordingly, two classes of new alkoxyphenylpiperazinylheptylpyridazinones were designed and synthesized to evaluate the effect of the alkoxy substituent on affinity and selectivity. As expected, affinity increased with larger alkoxy groups. Affinity values are all comparable with that of the reference compound (prazosin), with the exception of compound 1c found 4.5-fold more active than prazosin.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2003

3D QSAR studies of the interaction between beta-tubulin and microtubule stabilizing antimitotic agents (MSAA). A combined pharmacophore generation and pseudoreceptor modeling approach applied to taxanes and epothilones.

Based on the conformer of paclitaxel extracted from the experimental tubulin structure, a pharmacophoric model has been generated and used to find the chemical features common to the taxane and epothilone classes of compounds. This original alignment has been translated into the experimental tubulin binding site obtaining an assembly subsequently submitted to the pseudoreceptor modeling approach. As a result, an original 3D QSAR model, able to evaluate, at a quantitative level, the relationships between the molecular structures and biological data of the studied compounds, has been obtained.

Antineoplastic Agents↗
PubMed2003

3D QSAR studies for the beta-tubulin binding site of microtubule-stabilizing anticancer agents (MSAAs): a pseudoreceptor model for taxanes based on the experimental structure of tubulin.

The antimitotic agent paclitaxel continues to play an important role in the cancer chemotherapy. However, its inefficacy on certain resistant cells and toxic side effects have led to the search of new taxanes with improved biological activity. By means of a pseudoreceptor modeling approach, we have developed a binding site model for a series of taxanes. It is the first 3D QSAR model derived from the experimentally determined tubulin structure obtained by electron crystallography studies. The model is able to correlate quantitatively the structural properties of the studied compounds with their biological data.

Antineoplastic Agents↗
PubMed2003

Novel hypotensive agents from Verbesina caracasana: structure, synthesis and pharmacology.

The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and/or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: (1) The structure determination of the active compounds by spectral data and a set of reactions; (2) The confirmation of the structures by a biogenetically oriented synthesis; (3) The study of the pharmacological profiles of the isolated drugs; (4) The synthesis of analogous and homologous products in the effort to shed some light on the structure-activity relationship. The metabolites of V. caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and/or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and/or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis.

Animals↗
PubMed2003

Small-molecule inhibitors of fibroblast growth factor receptor (FGFR) tyrosine kinases (TK).

Fibroblast growth factor receptors (FGFR) are members of a family of polypeptides synthesized by a variety of cell types during the processes of embryonic development and in adult tissues. FGFR have been detected in normal and malignant cells and are involved in biological events that include mitogenic and angiogenic activity with a consequent crucial role in cell differentiation and development. To activate signal transduction pathways, FGFR are coupled to fibroblast growth factors (FGF) and heparan sulfate (HS) proteoglycans to form a biologically fundamental ternary complex. Based on these considerations, a variety of inhibitors able to block the signaling cascade through a direct interaction with FGFR have been designed and investigated for their biological properties related to antiangiogenesis and antitumor activity. The purpose of this review is to focus on synthetic chemical approaches aimed at blocking tyrosine kinase (TK) receptors, members of the FGFR family. In particular, a literature survey aimed at summarizing on the structural properties that a compound should possess to show affinity toward FGFR is presented, and structure-activity relationships (SAR) on FGFR inhibitors are delined.

Angiogenesis Inhibitors↗
PubMed2002

Synthesis, molecular modeling studies, and pharmacological activity of selective A(1) receptor antagonists.

We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A(1) adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A(1) AR antagonists taken from the literature and a model of the putative A(1) receptor. The pharmacophore model consists of seven features and represents an improvement of the N(6)-C8 model, generally reported as the most probable pharmacophore model for A(1) AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A(1), A(2a), and A(3) AR, showing interesting antagonistic activity and A(1) selectivity.

Animals↗
PubMed2002

Alpha(1)-adrenoceptor antagonists. 4. Pharmacophore-based design, synthesis, and biological evaluation of new imidazo-, benzimidazo-, and indoloarylpiperazine derivatives.

As a part of a program aimed at discovering compounds endowed with alpha(1)-adrenoceptor (AR) blocking properties, in this paper we describe the synthesis and biological characterization of the compounds designed to fully match a three-dimensional pharmacophore model for alpha(1)-AR antagonists previously developed by our research group. Accordingly, the structure of trazodone (1), identified during a database search performed by using the model as a 3D query, was chosen as the starting point for this study and modified following suggestions derived from a literature survey. In particular, the triazolopyridine moiety of trazodone was replaced with different heteroaromatic rings (such as imidazole, benzimidazole, and indole), and a pyridazin-3(2H)-one moiety was inserted into the scaffold of the new compounds to increase the overall length of the molecules and to allow for a complete fit into all the pharmacophore features. Our aim was also to study the influence of the position of both the chloro and the methoxy groups on the piperazine phenyl ring, as well as the effect of the lengthening or shortening of the polymethylene spacer linking the phenylpiperazine moiety to the terminal heterocyclic portion. Compounds obtained by such structural optimization share a 6-(imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, or 6-(indol-1-yl)pyridazin-3(2H)-one as a common structural feature that represents an element of novelty in the SAR of arylpiperazine compounds acting toward alpha(1)-AR. Biological evaluation by radioligand receptor binding assays toward alpha(1)-AR, alpha(2)-AR, and 5-HT(1A) serotoninergic receptors indicated compounds characterized by very good alpha(1)-AR affinity and selectivity. Very interestingly, chemical features (such as the o-methoxyphenylpiperazinyl moiety and an alkyl spacer of three or four methylene units) that generally do not allow for 5-HT(1A)/alpha(1) selectivity led to compounds 2c and 6c with a 5-HT(1A)/alpha(1) ratio of 286 and 281, respectively. Finally, compounds with the best alpha(1)-AR affinity profile (2c, 5f, and 6c) were demonstrated to be alpha(1)-AR antagonists.

Adrenergic alpha-Antagonists↗
PubMed2002

Enantioselective guest exchange in a chiral resorcin[4]arene cavity.

Gas-phase proton-bound complexes between a chiral resorcin[4]arene and some representative amino acids, that is, L- and D-alanine or L- and D-serine, were generated in the source of a Fourier transform ion cyclotron resonance mass spectrometer. Gas-phase exchange of the amino acid from the diastereomeric complexes with the enantiomers of 2-butylamine exhibits a significant enantioselectivity, which depends not only upon the configuration of the leaving guest but also on that of the incoming amine. These findings, coupled with molecular dynamic calculations, point to the observed gas-phase enantioselectivity as determined by the effects of the resorcin[4]arene chiral cavity upon the diastereomeric exchange transition structures.

Alanine↗
PubMed2002

Antifungal agents. 10. New derivatives of 1-[(aryl)[4-aryl-1H-pyrrol-3-yl]methyl]-1H-imidazole, synthesis, anti-candida activity, and quantitative structure-analysis relationship studies.

The synthesis, anti-Candida activity, and quantitative structure-activity relationship (QSAR) studies of a series of 2,4-dichlorobenzylimidazole derivatives having a phenylpyrrole moiety (related to the antibiotic pyrrolnitrin) in the alpha-position are reported. A number of substituents on the phenyl ring, ranging from hydrophobic (tert-butyl, phenyl, or 1-pyrrolyl moiety) to basic (NH(2)), polar (CF(3), CN, SCH(3), NO(2)), or hydrogen bond donors and acceptor (OH) groups, were chosen to better understand the interaction of these compounds with cytochrome P450 14-alpha-lanosterol demethylase (P450(14DM)). Finally, the triazole counterpart of one of the imidazole compounds was synthesized and tested to investigate influence of the heterocyclic ring on biological activity. The in vitro antifungal activities of the newly synthesized azoles 10p-v,x-c' were tested against Candida albicans and Candida spp. at pH 7.2 and pH 5.6. A CoMFA model, previously derived for a series of antifungal agents belonging to chemically diverse families related to bifonazole, was applied to the new products. Because the results produced by this approach were not encouraging, Catalyst software was chosen to perform a new 3D-QSAR study. Catalyst was preferred this time because of the possibility of considering each compound as a collection of energetically reasonable conformations and of considering alternative stereoisomers. The pharmacophore model developed by Catalyst, named HYPO1, showed good performances in predicting the biological activity data, although it did not exhibit an unequivocal preference for one enantiomeric series of inhibitors relative to the other. One aromatic nitrogen with a lone pair in the ring plane (mapped by all of the considered compounds) and three aromatic ring features were recognized to have pharmacophoric relevance, whereas neither hydrogen bond acceptor nor hydrophobic features were found. These findings confirmed that the key interaction of azole antifungals with the demethylase enzyme is the coordination bond to the iron ion of the porphyrin system, while interactions with amino acids localized in proximity of heme could modulate the biological activity of diverse antifungal agents. In conclusion, HYPO1 conveys important information in an intuitive manner and can provide predictive capability for evaluating new compounds.

Antifungal Agents↗
PubMed2002

Synthesis and interaction with copper(II) cations of cyano- and aminoresorcin[4]arenes.

Following our studies on resorcin[4]arenes, we synthesized new macrocycles containing cyanomethyl and aminomethyl side chains. Three stereoisomers (2a-c) of the former were obtained by BF3*Et2O tetramerization of the corresponding trans-cinnamic acid derivative and were shown to be in the 1,2-alternate, cone, and 1,3-alternate conformations. Conversely, the tetraamino derivative 6a in the cone conformation was prepared from the corresponding tetrabromide 3a. The interactions with Cu(II) cations of the new compounds were analyzed by measurements of 1H NMR and EPR spectra in parallel with molecular modeling calculations.

Journal Article↗
PubMed2002

alpha(1)-Adrenoceptor antagonists. Rational design, synthesis and biological evaluation of new trazodone-like compounds.

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

Molecular modeling as a powerful technique for understanding small-large molecules interactions.

In the present review we summarize recent work, aimed at a better understanding of the interactions in macromolecule ligand complexes, performed by means of computational tools such as pseudoreceptor generation, molecular docking, conformational search and energy minimization. While the first approach has been applied when the three-dimensional structural properties of the biological target were unknown, the remaining protocols exploited the knowledge of the overall structure of the involved macromolecules and their active sites. Molecular modeling techniques were used in the cases reported to study and propose macromolecular binding sites and to predict their interactions with bioactive conformers of the ligands.

Anti-HIV Agents↗
PubMed2002

Synthesis and biological activity of new 1,4-benzodioxan-arylpiperazine derivatives. Further validation of a pharmacophore model for alpha(1)-adrenoceptor antagonists.

A series of WB4101 (1)-related benzodioxanes (2-17) have been synthesized by replacing the phenoxyethyl moiety of 1 with a N-alkyl piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. The binding profile of these compounds has been assessed by radioligand receptor binding assay at alpha(1)- and alpha(2)-adrenoceptors, in comparison to prazosin and rauwolscine, respectively. Moreover, structure-activity relationships have been derived for compounds 2-17 based on their fitting to a pharmacophore model for alpha(1)-adrenoceptor antagonists recently proposed by our research group. In a parallel way, the same compounds have been used to further test the predictive power and statistical significance of the model itself. The accuracy of the results obtained also in this case revealed the robustness of the calculated pharmacophore model and led to the identification of the molecular structural moieties which are thought to contribute to the biological activity.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

A new and efficient synthesis of substituted 6-[(2'-dialkylamino)ethyl] pyrimidine and 4-N,N-dialkyl-6-vinyl-cytosine derivatives and evaluation of their anti-rubella activity.

New 6-[(2'-dialkylamino)ethyl]-4(3H)-pyrimidinones were prepared by a multistep procedure starting from acetone dicarboxylic acid diethyl ester and urea derivatives. These compounds were used as starting materials to obtain 4-N,N-dialkyl-6-vinyl-pyrimidine derivatives by an unprecedented tandem C-6 side chain Hofmann-like elimination/C-4 pyrimidinone substitution. Among the new derivatives obtained, various compounds show anti-Rubella activity. The inhibition of HIV-1 Reverse Transcriptases (RT), from both wild type and modified viruses, is also reported.

Antiviral Agents↗
PubMed1999

Cyclic Dipeptides. 3.(1) Synthesis of Methyl (R)-6-[(tert-Butoxycarbonyl)amino]-4,5,6,7- tetrahydro-2-methyl-5-oxo-1,4-thiazepine-3-carboxylate and Its Hexahydro Analogues: Elaboration of a Novel Dual ACE/NEP Inhibitor.

Synthetic routes to highly functionalized 1,4-thiazepinones 2 and 3 have been developed. S-Ac-N-Boc-L-Cys-D(L)-ThrOMe 7a,b have been prepared and, after transformation into the corresponding mesylates, used as the cyclization substrates. Treatment of these compounds with LiAlH(OMe)(3) in THF results in mesylate elimination and thiolacetate reduction, giving rise to both a Michael acceptor (alpha,beta-unsaturated ester) and Michael donor (thiol anion), which undergo in situ intramolecular conjugate addition leading to the stereoselective formation of only two of the four possible stereoisomers of 2. On the other hand, PCC/CaCO(3) oxidation of 7a gave in 80% yield the corresponding ketone 11, which was in turn transformed into the enol triflate 15. Cleavage of the thiolacetate moiety, simultaneous elimination of trifluoromethanesulfonic acid to generate an allene system, and addition of the thiol group to the central carbon of the allene to provide the enantiomerically pure cyclic compound 3 in 85% yield was effected via a one-pot reaction by means of MeONa/MeOH. Thiazepinone 3 is an interesting intermediate for the preparation of conformationally restricted dipeptide mimetics, and its elaboration into the dual ACE/NEP inhibitor 4 is reported.

Journal Article↗