Carboxyl Group In Position Research Articles

Synthesis and biological evaluation of novel quinoline analogs of ketoprofen as multidrug resistance protein 2 (MRP2) inhibitors.

Objective(s):A new series of quinoline analogs of ketoprofen was designed and synthesized as multidrug resistance protein 2 (MRP2) inhibitors using ketoprofen as the lead compounds.Materials and Methods: The cytotoxic activity of the compounds was evaluated againt two cancer cell lines including A2780/RCIS (MRP2-overexpressing ovarian carcinoma), A2780, drug-sensitive ovarian carcinoma using MTT assay. Compounds showing low toxicity in MTT test were selected to investigate their MRP inhibition activity. MRP2 inhibitory potency was evaluated by determination of the uptake amount of fluorescent 5-carboxy fluorescein diacetate (5-CFDA) substrate, by A2780/RCIS in the presence of the selected compounds. Mode of interaction between synthesized ligands and homology modeled MRP2 was investigated by MOE software. Results:Compound 6d, a 4-carboxy quinoline possessing dimethoxy phenyl in position 2 of quinoline ring, showed the most MRP2 inhibition activity among all the quinolines and more than the reference drug ketoprofen. MRP2 inhibition activity of compound 7d was less in comparison to that of compound 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2. Docking studies showed that compound 7d methyl ester of 6d, interacted less compared to its parent 6d, which is consistent with biological results.Conclusion:This study indicates that 6- or 8-benzoyl-2-arylquinoline is a suitable scaffold to design MRP2 inhibitors. The position of benzoyl in quinoline ring is important in inhibition of MRP2. Generally, MRP2 inhibition activity of compound 7d was less in comparison to that of 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2.

Identification of structural features of ursolic acid required to protect monocytes against metabolic stress‐induced dysfunction (249.5)

We showed that ursolic acid (UA), a pentacyclic triterpenoid with anti‐inflammatory properties, reduces atherosclerotic lesion size and improves kidney function in diabetic mice. We proposed that the atheroprotective effects of UA are due to its ability to protect monocytes against metabolic stress‐induced dysfunction or “priming”, i.e. the Nox4‐mediated hyper‐responsiveness to chemokine‐induced cell adhesion and migration. The aim of this study was to test eight of UA’s naturally occurring structural analogs and identify the structural features of UA required to inhibit monocyte priming. We determined in metabolically primed THP‐1 monocytes the doses (0.03 ‐ 3 μM) at which UA and its analogues blocked metabolic stress‐induced Nox4 induction and accelerated chemotaxis in response to MCP‐1. Only the UA analogs uvaol and corosolic acid protected monocytes against metabolic priming. We found that altering the position of one methyl group in position 19 of UA abolishes its protective effects. Furthermore, the carboxyl group in position 17 appears to be critical but not sufficient for UA to prevent monocyte priming by metabolic stress. In summary, our data suggest a highly selective molecular mechanism for the protective effects of UA on monocyte priming and dysfunction and UA’s anti‐atherogenic properties. Identifying the functional groups responsible for UA’s beneficial effects will allow us to develop more potent, low‐cost dietary supplements for the prevention of atherosclerosis and other monocyte‐mediated diabetic complications.Grant Funding Source: Supported by grants to RA from the NIH (R01‐AT006885)

ChemInform Abstract: Regioselective Synthesis of Pyrrolin‐3‐ones and 2,3,4,5‐Tetrahydro[1,3]‐oxazines from N‐Vinylic Amidines.

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Regioselective synthesis of pyrrolin-3-ones and 2,3,4,5-tetrahydro[1,3]-oxazines from N-vinylic amidines

Achiral and optically active N-vinylic amidines are obtained by simple addition of amidines to acetylenic esters. Thermal intramolecular cyclization of these substrates containing a carboxylate group in position 3 gives pyrrolin-3-ones. The enaminone character of these compounds towards propargyl bromide, diethyl azodicarboxylate, diethyl acetylenedicarboxylate, ethyl propiolate and phenyl isocyanate is studied and functionalized pyrrolin-3-one derivatives are obtained. The reaction of the pyrrolinones prepared with diethyl ketomalonate leads to new 1,3-oxazine derivatives.

Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity.

In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS(50) 4 and 5 micromol/L) and seco-anhydrides 22 and 23 (TCS(50) 7 and 6 micromol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).

13 C NMR spectra of some indole derivatives

The effect of acyl and carboxyl groups in position 2 or 3 of the indole ring on the13C chemical shifts of the ring was studied, α-, β-, and γ-Increments of the indole and isatin rings for13 C chemical shifts of the substituants at the ring N-atom were determined.

Topographical requirements for delta opioid ligands: Presence of a carboxyl group in position 4 is not critical for deltorphin high delta receptor affinity and analgesic activity

To investigate the role of the carboxyl group in deltorphin molecules, we have synthesized three new analogues in which the acidic amino acid residues in position 4 of the deltorphins were replaced by non-acidic but hydrophilic amino acids residues. The three analogues, [Ser4]-, [Gln4]-, and [Cys4]-deltorphin, all are as potent or more potent than either deltorphin I or II at delta opioid receptors and possess good delta selectivities. The excellent correlation between their in vitro delta receptor potencies and their intrathecal antinociception activity forms a strong argument for involvement of those receptors in spinal nociceptive modulation in the rats.

Effect of Covalent Dimer Conjugates of Angiotensin II on Receptor Affinity and Activity in Vitro

Angiotensin II [1-8 or 2-8] analogues and [4-8] fragments were dimerized through the amino- or carboxy-terminal groups in order to try to increase their potency as reported for other hormones. The binding affinity to the angiotensin II receptor subtypes A (A IIA) and B (A IIB) was tested and compared to the potency in rabbit aortic ring. The [2-8] dimers coupled through the N-terminus show no significant change in potency in aortic ring. The [4-8] fragments coupled through the N-terminus are inactive in the ring. They have however a significantly increased affinity for the A IIA receptor, the specific function of which has not yet been reported. When angiotensin II analogues or fragments are coupled through the C-terminus, there was a significant drop in affinity and potency, confirming the importance of the free carboxyl group in position 8 for binding and activity. It is concluded that binding to the A IIB receptor correlates well with the effectiveness in aortic ring. However, in contrast to the beneficial effect reported for a large number of other hormones, dimerization of angiotensin II or its fragments is not accompanied by an increased biological activity in aortic ring.

Potential antihistaminics: Tricyclic carboxylic acids derived from 6,11-dihydrodibenzo[b,e]thiepine and 4,9-dihydrothieno[2,3-c]-2-benzothiepine

Reaction of nitrile IVa with the Grignard’s reagent 1-methyl-4-piperidylmagnesium chloride gave carbinol XIb as product. Carbinols XIa and XIb were dehydrated and hydrolysed with dilute hydrochloric acid to give hydrochlorides of the tricyclic amino acids Vb and Vc. Isomeric compounds with a carboxyl group in position 9 of the tricyclic skeleton were obtained either by hydrolysis of the formely prepared nitrile VIIb (compound VIIIb) or on reaction of bromoketone VIa with 1-methyl-4-piperidylmagnesium chloride, nucleophilic substitution of the bromine atom by the cyano group at the stage of carbinol XIIIb, and subsequent dehydration and hydrolysis of the cyano group, to give amino acid VIIIc. In the first case the synthesis of thiophene analogues XVIIIb and XVIIIc started from ketone XVa, which was brominated with bromine in acetic acid into position 2 of the tricyclic skeleton, followed by Grignard’s reaction with 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran and hydrolysis to bromo derivative XVIb. In the second case derivative XVIc was obtained directly by bromination of hydrochloride XVc. Basic bromo derivatives XVIb and XVIc were reacted with butyllithium in tetrahydrofuran at –60°C to afford corresponding organometallic reagents which, when reacted with solid carbon dioxide, afforded the required amino acids XVIIIb and XVIIIc. Further, some other tricyclic nitriles were synthesized as potential intermediates. The prepared tricyclic amino acids Vb, Vc, VIIIb, VIIIc, XVIIIb and XVIIIc were tested both on animals and in assays of biochemical pharmacology. Some of them displayed considerable antihistaminic activity. The most interesting compound of this series, hydrochloride Vc (VUFB-17689) is a strong antihistaminic with distinctly suppressed sedative effects and it was therefore selected for a more detailed pharmacological testing.

NMR studies of the complexes of uramildiacetic acid

Proton spectra of 1,3 dimethyluramildiacetic acid and its complexes with several lanthanide ions as well as titration curves of uramildiacetic and barbituric acids where 13C chemical shifts were followed as a function of pH, have enabled the establishment of the conformation in solution of the complexes of the uramildiacetate-type ligands and of the most probable mechanism of ionization of these compounds. It is definitely shown that uramildiacetic acid is tetradentate and that it coordinates to metal ions through the iminodiacetate group and one of the carboxyl groups in position 4,6 of the molecule. The pyrimidinic ring and one of the chelator rings are coplanar and the complexes have axial symmetry. As a side result it is shown that barbituric acid is diprotic and its second ionization constant, p k 2, is approx. 12; the same happens with 5,5 barbiturates.

2,4-Diamino-5-(3,5-dimethoxy-4-substitute)-benzylpyrimidines as ligands in affinity chromatography of bacterial dihydrofolate reductases

Inhibitors of the trimethoprim-type, bearing terminal amino, hydroxyl or carboxyl groups in position 4 of the benzene ring as well as methotrexate were coupled to either CH-Sepharose 4B, epoxy-activated Sepharose 6B or AH-Sepharose 4B, respectively. In contrast to the methotrexate-affinity gel, trimethoprim-like ligands retained bacterial but not mammalian dihydrofolate reductases. The affinity gels prepared with these ligands could be used for effective purification of bacterial dihydrofolate reductases (EC 1.5.1.3), but differed in their affinity for this enzyme.

The structure of melanins and melanogenesis—III : The structure of sepiomelanin

New degradation products of sepiomelanin have been obtained. Alkali fusion yields, in addition to other compounds, 5,6-dihydroxyindole, 5,6-dihydroxyindole-2-carboxylic acid, 4-methyl-cathechol and a compound, which is probably 5,6-dihydroxyindole-4,7-dicarboxylic acid. These products constitute the first proof of the indole structure of a natural melanin. The carboxyl group of 5,6-dihydroxyindole-2-carboxylic acid is not formed during alkali fusion, but pre-exists in the macromolecule. Cysteic acid, taurine, glycine and aspartic acid were obtained by oxidation of sepiomelanin with hydrogen peroxide in acetic acid. The formation of cysteic acid indicates that sepiomelanin is bound to the protein by means of cysteine. Taurine is clearly an artifact generated by decarboxylation of cysteine. Glycine and aspartic acid probably are derived from the pyrrole moiety of the indole units: they also result from the oxidation of 5,6-dihydroxyindole-2-carboxylic acid. Oxidation of methylated sepiomelanin yields 3-carbomethoxypyrrole-2,5-dicarboxylic acid and 5-carbomethoxypyrrole-2,3-dicarboxylic acid; isolation of the former further proves the presence of pyrrole units in sepiomelanin, whereas formation of the latter is further evidence that some indole (probably dopachrome) units of the macromolecule have a carboxyl group in position 2.

The structure of melanins and melanogenesis—II

A comparative study on sepiomelanin and three synthetic pigments, namely dopa melanin, 5,6-dihydroxyindole melanin and pyrrole black, has been carried out. Sepiomelanin is structurally related to 5,6-dihydroxyindole and dopa melanins. The only observed differences are the absence of carboxyl groups in position 2 of the indole nuclei in the synthetic pigments (this result, obvious for 5,6-dihydroxyindole melanin, is rather surprising for dopa melanin) and the presence of α-amino acid chains in dopa melanin. Some carboxyl groups found in dopa and 5,6-dihydroxyindole melanins are located on pyrrole units. Considerable differences arise when comparing pyrrole black with sepiomelanin.