New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives (original) (raw)
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Synthesis of Diaryl-Substituted Imidazo[1,2-a]pyridines Designed as Potential Aromatase Inhibitors
CHEMICAL & PHARMACEUTICAL BULLETIN, 2000
From a pharmacophore model of bicyclic heterocycles as aromatase inhibitors we have designed three series of imidazo[1,2-a]pyridine derivatives. The synthesis and the spectroscopy determination of various compounds are reported. The crystal data of one of these compounds (10b) was obtained. The aromatase inhibition potency was evaluated in vitro and no activity was found.
Bioorganic & Medicinal Chemistry Letters, 1999
Six azolyl substituted indoles were synthesized and tested for their activity to inhibit two P450 enzymes: P450 arom and P450 17or. It was observed that the introduction of c~-imidazolylbenzyl chain at carbon 3 or 5 on indole nucleus led to very active molecules. Compounds 22, 23 and especially 33 demonstrate very high potential against P450 atom Under our assay conditions of high substrate concentration the ICs0 are 0.057, 0.0785 and 0.041 BM, respectively. These compounds are moderate inhibitors against P450 17o~.
Enantioselectivity of aromatase inhibitors: Substituted 3-(4-aminophenyl)pyrrolidine-2,5-diones
Chirality, 1995
The (+I-, (-)-, and (+)-forms of 1and 1,3-substituted 3-(4-aminophenyl)pyrrolidine-2,5-dione have been examined as inhibitors of P450AKOM and P45OcScc. The mhlbitory potency for P450AKOM resided in the (+I-enantiomers of (l), (21, and (4) and the (-)-enantiomus of (3) and (5). These findings have been accommodated within a molecular graphics-derived model for binding of P450AKC)M inhibitors to the substrate binding site. Crystallography showed that (+I421 has the (R)-configuration. Spectral binding studies with human placental P450.4KOM showed type I1 binding but although the Ks values were in line with the IC,,, values for individual compounds there was no overall correlation between Ks and IC,, within the series. There was little difference in the inhibitory potency of the enantiomers and racemate of individual compounds toward P45OcScc.
Journal of Medicinal Chemistry, 2001
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 sitea 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 pairwere 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 ,2 -3 H]testosterone as the labeled substrate. All the compounds were also tested on 17R-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. Figure 3. HOMO of compounds 22l (a) and 22m (b), showing the localization of the orbital over the imidazole ring and over the xanthone nucleus, respectively.
Biochemical and Biophysical Research Communications, 2000
A novel molecular modeling study, involving inhibitors bound to the iron of cytochrome P450 heme, is described for nonsteroidal inhibitors of aromatase (AR). Study of compounds such as aminoglutethimide (AG) suggests that it utilizes hydrogen bonding group(s) at the active site which would usually H-bond to the steroid C(17) carbonyl group. Interaction between AG's carbonyl groups and the area of the active site corresponding to the substrate C(3)AO group is not possible due to steric interaction. Possible reasons for the difference in activity of enantiomers of alternative inhibitors is also suggested, as well as the mode of action of the new AR inhibitor, Arimidex-whose inhibitory activity previously has not been rationalized. The present study proposes that it is able to use hydrogen bonding groups at the active site corresponding to the steroid C(17)AO and C(3)AO area, contradicting a previous study where it is postulated that azole-type compounds only use polar groups at the active site corresponding to the steroid D ring. Using the hypotheses of the modeling study, we designed and synthesized a number of novel (enantiomerically pure) inhibitors, which upon biochemical evaluation were found to be good inhibitors; the N-nonyl derivative of the S-enantiomer was found to possess 39% inhibition at 100 M inhibitor concentration (using androstenedione as the substrate), under similar conditions, and AG possessed 20% inhibition.
MR 20492 and MR 20494: two indolizinone derivatives that strongly inhibit human aromatase
Journal of Steroid Biochemistry and Molecular Biology, 1999
In this study, we describe the synthesis of a new family of indolizinone derivatives designed to fit an extrahydrophobic pocket within the active site of aromatase and to strongly inhibit human aromatase. This could help improve the specificity of the inhibitors. Equine aromatase, very well characterized biochemically, is used as a comparative model. Indeed, in a previous comparison between both
Journal of Medicinal Chemistry, 2013
A small library of both [2,3-h] and [3,2-f ] novel pyrroloquinolines equipped with an azolylmethyl group was designed and synthesized as nonsteroidal CYP19 aromatase inhibitors. The results showed that azolylmethyl derivatives 11, 13, 14, 21, and 22 exhibited an inhibitory potency on aromatase comparable to that of letrozole chosen as a reference compound. When assayed on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase), compound 22 was found to be the best and most selective CYP19 inhibitor of them all. In a panel of nine human cancer cell lines, all compounds were either slightly cytotoxic or not at all. Docking simulations were carried out to inspect crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding, and heme iron coordination. This study, along with the prediction of the pharmacokinetics of compounds 11, 13, 14, 21, and 22, demonstrates that the pyrroloquinoline scaffold represents a starting point for the development of new pyrroloquinoline-based aromatase inhibitors.
2019
In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0-72 h), starting from a concentration of 100 μM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.