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1.
Curr Med Chem ; 20(13): 1759-82, 2013.
Article in English | MEDLINE | ID: mdl-23410171

ABSTRACT

Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.


Subject(s)
Cardiovascular Agents/chemistry , Cardiovascular Agents/pharmacology , Cardiovascular Diseases/drug therapy , Cardiovascular System/drug effects , Drug Design , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cardiovascular System/metabolism , Cardiovascular System/pathology , Humans , Hypertension/drug therapy , Molecular Targeted Therapy/methods , Renin-Angiotensin System/drug effects
3.
J Med Chem ; 44(23): 3810-20, 2001 Nov 08.
Article in English | MEDLINE | ID: mdl-11689067

ABSTRACT

In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.


Subject(s)
Acetylcholinesterase/chemistry , Carbamates/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Acetylcholinesterase/metabolism , Butyrylcholinesterase/chemistry , Carbamates/chemistry , Cholinesterase Inhibitors/chemistry , Humans , Kinetics , Models, Molecular , Protein Binding , Quantum Theory , Structure-Activity Relationship
4.
Cell Biochem Funct ; 19(3): 181-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11494307

ABSTRACT

Geiparvarin is an antiproliferative compound isolated from the leaves of Geijera parviflora, and may represent a new drug which targets tubulin. To better explore the potential use of this agent, we investigated the antimicrotubular and cytotoxic effects of new synthetic aromatic derivatives of geiparvarin. These drugs inhibited polymerization of microtubular protein, particularly when the assembly was induced by paclitaxel. The microtubular network organization of fibroblasts was altered more effectively by some drugs. Normal microtubule architecture completely disappeared when the cells were treated simultaneously with drugs and paclitaxel: microtubules depolymerized or were reorganized into bundles, in a similar but more disarrayed fashion than that observed after treatment with paclitaxel alone. Cytotoxicity studies showed a dose-dependent effect, whereas combined administration of drugs and paclitaxel increased cytotoxicity, more effectively in paclitaxel versus derivatives administration alone.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Coumarins/pharmacology , Microtubules/drug effects , Paclitaxel/pharmacology , Tubulin/drug effects , 3T3 Cells , Animals , Cell Division/drug effects , Cytoskeleton/drug effects , Growth Inhibitors/chemistry , Mice , Mice, Inbred BALB C , Structure-Activity Relationship , Tubulin/chemistry
5.
J Med Chem ; 44(5): 672-80, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11262078

ABSTRACT

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.


Subject(s)
Aromatase Inhibitors , Chromones/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Xanthenes/chemical synthesis , Xanthones , Chromones/chemistry , Chromones/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Male , Microsomes/drug effects , Microsomes/enzymology , Models, Molecular , Placenta/ultrastructure , Structure-Activity Relationship , Testis/ultrastructure , Xanthenes/chemistry , Xanthenes/pharmacology
6.
Bioorg Med Chem ; 8(1): 239-46, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10968283

ABSTRACT

Some rigid analogues of flavone-8-acetic acid are described. Direct in vitro toxicity of the synthesised compounds was evaluated towards four tumoral cell lines and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. All compounds were able to induce direct cytotoxicity only at very high concentrations but showed a remarkable indirect activity. In particular compound 4d was able to significantly increase macrophage lytic properties and has been selected for further investigations.


Subject(s)
Flavonoids/chemical synthesis , Flavonoids/pharmacology , Animals , Cell Division/drug effects , Cells, Cultured , Flavonoids/toxicity , Humans , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Magnetic Resonance Spectroscopy , Mice , Tumor Cells, Cultured
7.
J Med Chem ; 43(10): 2007-18, 2000 May 18.
Article in English | MEDLINE | ID: mdl-10821713

ABSTRACT

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.


Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Structure-Activity Relationship , Tacrine/analogs & derivatives , Chemical Phenomena , Chemistry, Physical , Erythrocytes/enzymology , Humans , Models, Chemical , Models, Molecular , Molecular Conformation , Software , Static Electricity , Tacrine/chemical synthesis , Tacrine/pharmacology
8.
Bioorg Med Chem ; 8(3): 497-506, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10732965

ABSTRACT

Continuing our work on tetracyclic tacrine analogues, we synthesized a series of acetylcholinesterase (AChE) inhibitors of 11H-indeno-[1,2-b]-quinolin-10-ylaminic structure. Selected substituents were placed in synthetically accessible positions of the tetracyclic nucleus, in order to explore the structure-activity relationships (SAR) and the mode of action of this class of anticholinesterases. A molecular modeling investigation of the binding interaction of the lead compound (1a) with the AChE active site was performed, from which it resulted that, despite the rather wide and rigid structure of 1a, there may still be the possibility to introduce some small substituent in some positions of the tetracycle. However, from the examination of the experimental IC50 values, it derived that the indenoquinoline nucleus probably represents the maximum allowable molecular size for rigid compounds binding to AChE. In fact, only a fluorine atom in position 2 maintains the AChE inhibitory potency of the parent compound, and, actually, increases the AChE-selectivity with respect to the butyrylcholinesterase inhibition. By studying the kinetics of AChE inhibition for two representative compounds of the series, it resulted that the lead compound (1a) shows an inhibition of mixed type, binding to both the active and the peripheral sites, while the more sterically hindered analogue 2n seems to interact only at the external binding site of the enzyme. This finding seems particularly important in the context of Alzheimer's disease research in the light of recent observations showing that peripheral AChE inhibitors might decrease the aggregating effects of the enzyme on the beta-amyloid peptide (betaA).


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Aminoquinolines/chemistry , Animals , Binding Sites , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Computer Simulation , Electrons , Indenes/chemistry , Inhibitory Concentration 50 , Kinetics , Ligands , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Tacrine/metabolism , Torpedo
9.
Eur J Pharmacol ; 359(2-3): 161-70, 1998 Oct 23.
Article in English | MEDLINE | ID: mdl-9832387

ABSTRACT

The effect of the dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(fluorenon-4-yl)pyridine-3,5-dicarboxyl ic acid diallyl ester (fluodipine) was studied in vitro in different rabbit, rat and guinea pig preparations and in vivo in the rabbit in order to characterize its pharmacological profile at cardiac and at vascular sites. Compared to nifedipine, fluodipine showed a similar cardiodepressant activity, and a much lower inhibitory activity on vascular contraction. The highest tissue selectivity was observed in guinea pig preparations: fluodipine was about 2-3 times more effective than nifedipine on chronotropism and inotropism in isolated atria, and about 150 times less effective on aortic strip contraction. Accordingly, fluodipine (i) showed high-affinity binding to guinea pig ventricular L-type cardiac Ca2+ channels (Ki=2.57 nM), (ii) was about 80 times less effective than nifedipine to inhibit Ca2+ influx in vascular smooth muscle cells and (iii) induced a significant reduction of heart rate in the anesthetized rabbit (ID25=8.5 mg kg(-1), i.v.) without affecting the blood pressure up to 20 mg kg(-1), whereas nifedipine showed a significant hypotensive effect at very low doses (ID25=0.18 mg kg(-1), i.v.). The pacemaker current If of rabbit sino-atrial node myocytes was not affected by fluodipine. These findings demonstrate that fluodipine exerts selective cardiodepressant activity, likely due to a higher affinity for cardiac than for vascular Ca2+ channels.


Subject(s)
Calcium Channel Blockers/pharmacology , Dicarboxylic Acids/pharmacology , Dihydropyridines/pharmacology , Vasodilator Agents/pharmacology , Anesthesia , Animals , Aorta/drug effects , Aorta/physiology , Atrial Function , Binding, Competitive , Blood Pressure/drug effects , Calcium/metabolism , Calcium Channel Blockers/metabolism , Calcium Channels/metabolism , Dicarboxylic Acids/chemistry , Dicarboxylic Acids/metabolism , Dihydropyridines/chemistry , Dihydropyridines/metabolism , Electrophysiology , Female , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , In Vitro Techniques , Male , Membrane Potentials/drug effects , Myocardial Contraction/drug effects , Myocardium/cytology , Myocardium/metabolism , Nifedipine/metabolism , Nifedipine/pharmacology , Pacemaker, Artificial , Patch-Clamp Techniques , Rabbits , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sinoatrial Node/drug effects , Sinoatrial Node/physiology , Vasoconstriction/drug effects
10.
J Med Chem ; 41(21): 3976-86, 1998 Oct 08.
Article in English | MEDLINE | ID: mdl-9767635

ABSTRACT

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.


Subject(s)
Acetylcholinesterase/metabolism , Carbamates/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Xanthenes/chemical synthesis , Xanthones , Animals , Binding Sites , Butyrylcholinesterase/metabolism , Carbamates/chemistry , Carbamates/metabolism , Carbamates/pharmacology , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , In Vitro Techniques , Kinetics , Models, Molecular , Rats , Rats, Wistar , Structure-Activity Relationship , Xanthenes/chemistry , Xanthenes/metabolism , Xanthenes/pharmacology
11.
Bioorg Med Chem ; 6(6): 803-10, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9681146

ABSTRACT

A series of 1,4-dihydropyridines bearing a coumarin moiety in 4-position was synthesized. The compounds were evaluated for inotropic, chronotropic and calcium antagonist activities. The replacement of the o-nitrophenyl moiety of nifedipine with a coumarin or phenylcoumarin system is accompanied by a decrease of the activity on myocardial and vascular parameters, but the synthesized compounds showed selective inhibiting effects on cardiac contractility and frequency.


Subject(s)
Calcium Channel Blockers/chemical synthesis , Coumarins/chemical synthesis , Dihydropyridines/chemical synthesis , Heart/drug effects , Vasodilator Agents/chemical synthesis , Animals , Aorta/drug effects , Aorta/physiology , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Depression, Chemical , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Female , Guinea Pigs , Heart/physiology , Heart Rate/drug effects , In Vitro Techniques , Male , Myocardial Contraction/drug effects , Stereoisomerism , Structure-Activity Relationship , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacology
12.
Anticancer Drug Des ; 13(8): 881-92, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10335265

ABSTRACT

Some flavone-2'-carboxylic acid analogues are described. Direct in vitro toxicity of the synthesized compounds was evaluated towards four tumoral cell lines, and the ability of these compounds to stimulate mouse peritoneal macrophages in culture to become tumoricidal (indirect toxicity) was also studied. Direct cytotoxic activity was very low for all derivatives. However, almost all compounds showed a remarkable increase of indirect cytotoxicity. In particular, compound 3i, which has an F atom in the 7 position of the flavone ring, was able to increase significantly the macrophage's lytic properties, and has been selected for further investigations.


Subject(s)
Antineoplastic Agents/chemical synthesis , Carboxylic Acids/chemistry , Flavonoids/chemistry , Adjuvants, Immunologic/chemical synthesis , Adjuvants, Immunologic/pharmacology , Animals , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Flavonoids/pharmacology , Humans , Macrophages, Peritoneal/drug effects , Mice , Structure-Activity Relationship , Tumor Cells, Cultured/drug effects
13.
Anticancer Drug Des ; 12(6): 443-51, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9311554

ABSTRACT

Some simple geiparvarin analogues, in which the coumarin moiety has been replaced with an X-substituted benzene ring, are described. The compounds were tested on LoVo cells (human colon carcinoma cell line) and some of them show a cytotoxicity comparable with that of the prototype. A QSAR analysis was also attempted, but it did not provide satisfactory results, mainly because of the limited range of variation of the biological activity.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Coumarins/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Colonic Neoplasms/pathology , Coumarins/chemistry , Coumarins/pharmacology , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Structure-Activity Relationship , Tumor Cells, Cultured
14.
Arzneimittelforschung ; 47(7): 803-9, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9272235

ABSTRACT

With the aim to split the pharmacological properties of lefetamine (CAS 14148-99-3), some structural modifications of this compound have been studied. The basic group of lefetamine has been shifted from the alkyl chain to the vicinal phenyl ring and the N-substitution has been changed. The dimethylaminomethyl derivatives and chiefly the o-morpholinometyhl exhibited a strong anti-visceral chemical antinociception activity stripped of thermal antinociception properties and physical dependence liability. Furthermore, through the introduction of a diethylaminomethyl group in the lefetamine structure some derivatives were selected exhibiting besided a significant increase in the anti-visceral chemical antinociception activity, remarkable local anesthetic properties.


Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Anesthetics, Local/chemical synthesis , Anesthetics, Local/pharmacology , Phenethylamines/pharmacology , Analgesics, Non-Narcotic/toxicity , Anesthesia, Intravenous , Anesthetics, Local/toxicity , Animals , Anura , Behavior, Animal/drug effects , Female , Guinea Pigs , Lethal Dose 50 , Male , Mice , Pain Measurement/drug effects , Peripheral Nerves/drug effects , Phenethylamines/chemistry , Phenethylamines/toxicity , Rabbits , Structure-Activity Relationship , Substance-Related Disorders/psychology
15.
Anticancer Drug Des ; 12(2): 137-44, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9113068

ABSTRACT

Some geiparvarin bioisosteres and homologues are described. The compounds were tested on LoVo cells (human colon carcinoma cell line). The EC50 values of the synthesized compounds ranged from 35.04 microM (compound 3) to 11.88 microM (compound 4), while the EC50 value of geiparvarin 1 was 13.30 microM.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Colonic Neoplasms/drug therapy , Coumarins/chemical synthesis , Coumarins/pharmacology , Drug Screening Assays, Antitumor , Humans , Isomerism , Structure-Activity Relationship , Tumor Cells, Cultured
16.
Farmaco ; 52(1): 13-9, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9181675

ABSTRACT

The synthesis of a series of derivatives related to (+/-) cis 6a, 12a-dihydro-6H,7H-[1]-benzopyrano-[4,3-b]-[1]-benzopyran (Homopterocarpane) is described. The synthesized derivatives have been tested at National Cancer Institute in its in vitro anti-cancer and anti-AIDS screening programs. The synthesized compounds are inactive in anti-HIV assay, while some show a GI50 < 100 microM (and < 50 microM in several cell lines) in NCI antitumor screening.


Subject(s)
Anti-HIV Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzofurans/chemical synthesis , Benzopyrans/chemical synthesis , HIV-1/drug effects , Anti-HIV Agents/pharmacology , Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Benzopyrans/pharmacology , Drug Screening Assays, Antitumor , Humans , Tumor Cells, Cultured
17.
Anticancer Drug Des ; 12(8): 607-20, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9448701

ABSTRACT

Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of various tumour cell lines with a mechanism of action so far unknown. Our preliminary findings showed that geiparvarin and some derivatives obtained from its conjugation with diethylstilboestrol and meso-hexestrol significantly inhibit taxol-induced in vitro polymerization of both tubulin and microtubular protein. In this study we investigated the effect of geiparvarin and of the oestrogen-combined derivatives on the cellular microtubular network of fibroblasts. Geiparvarin altered the microtubular organization of fibroblasts and strengthened the derangement of the microtubular pattern in cells exposed simultaneously to taxol. However, the microtubular network remained quite well organized in fibroblasts exposed to geiparvarin and preincubated with taxol, which in this case prevented the deranging effect of the former. The antimicrotubular activity of the oestrogen-combined derivatives was more similar to that of geiparvarin than to that of the oestrogens, and often this activity was stronger than that of each reference drug alone; the cytotoxic activity examined in the same experimental conditions generally confirmed the microscopic analysis.


Subject(s)
3T3 Cells/drug effects , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Coumarins/pharmacology , Diethylstilbestrol/pharmacology , Microtubules/drug effects , Paclitaxel/pharmacology , Animals , Centrosome/drug effects , Drug Screening Assays, Antitumor , Mice
18.
Bioorg Med Chem ; 4(10): 1629-35, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8931932

ABSTRACT

A series of 1,4-dihydropyridines bearing a pharmacophoric fragment of lidoflazine was synthesized. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist activities. All compounds behave as inotropic and chronotropic agents, except for compounds 4b, 5a, and 5b, which exhibit a rather weak calcium antagonism in vascular smooth muscle (like aorta). Compound 5b is about twofold more potent in decreasing both chronotropy and inotropy, while compound 5c is about fivefold more potent in decreasing inotropy than nifedipine. Moreover, compound 5b is the most potent calcium antagonist derivative of the series.


Subject(s)
Calcium Channel Blockers/chemistry , Dihydropyridines/chemistry , Lidoflazine/chemistry , Vasodilator Agents/chemistry , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Calcium Channel Blockers/pharmacology , Dihydropyridines/pharmacology , Female , Guinea Pigs , Heart/drug effects , Lidoflazine/pharmacology , Male , Myocardial Contraction/drug effects , Vasodilator Agents/pharmacology
19.
Arzneimittelforschung ; 46(9): 848-51, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8876931

ABSTRACT

A series of xanthone-1,4-dihydrophyridine derivatives bearing a chlorine atom in the xanthone nucleus was prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties. The chlorine introduction in the xanthone moiety slightly affected affinity for cardiac vs. vascular tissues improving to some extent selectivity.


Subject(s)
Cardiovascular Agents/chemical synthesis , Dihydropyridines/chemical synthesis , Animals , Anti-Arrhythmia Agents/pharmacology , Aorta, Thoracic/drug effects , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacology , Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/pharmacology , Cardiovascular Agents/pharmacology , Chemical Phenomena , Chemistry, Physical , Dihydropyridines/pharmacology , Female , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Myocardial Contraction/drug effects , Organ Specificity
20.
Arzneimittelforschung ; 46(4): 374-7, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8740081

ABSTRACT

A series of xanthone and fluorenone-1,4-dihydropyridine derivatives bearing a 5-phosphonate group were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonistic properties. The insertion of a phosphonate group is detrimental for inotropic and calcium antagonistic activity but improves the potency and selectivity for chronotropism.


Subject(s)
Calcium Channel Blockers/chemical synthesis , Cardiotonic Agents/chemical synthesis , Dihydropyridines/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Animals , Aorta, Thoracic/drug effects , Calcium Channel Blockers/pharmacology , Cardiotonic Agents/pharmacology , Dihydropyridines/pharmacology , Female , Guinea Pigs , Heart Atria/drug effects , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Myocardial Contraction/drug effects , Organophosphorus Compounds/pharmacology , Structure-Activity Relationship
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