Download or read book Design Synthesis and Biological Evaluation of a Series of Novel Aromatase Inhibitors Using a P450AROM Comparative Model written by Mohammad Reza Saberi and published by . This book was released on 2003 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Synthesis and Biological Evaluation of Potential Aromatase Inhibitors for Treatment of Hormone dependent Breast Cancer written by Masoud Ahmadi and published by . This book was released on 1989 with total page 470 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Computer assisted Design Synthesis and Biological Evaluation of New Aromatase Inhibitors as Potential Anticancer Agents written by Angelo Danilo Favia and published by . This book was released on 2005 with total page 122 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Computational Investigations of Cytochrome P450 Aromatase Catalysis and Biological Evaluation of Isoflavone Aromatase Inhibitors written by John C. Hackett and published by . This book was released on 2004 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization are explored and determined to be unlikely. Mechanisms for the aromatization/deformylation sequence which are initiated by 1beta-hydrogen atom abstraction by P450 Compound I are considered. 1beta-Hydrogen atom abstraction from substrates in the presence of the 2,3-enol encounters strikingly low barriers, whereas barriers for this same process are higher in the keto tautomer. Transition states for 1beta-hydrogen atom abstraction from enolized substrates in the presence of the 19-gem-diol decayed directly to the experimentally observed products. If the C19 aldehyde remains unhydrated, aromatization occurs with concomitant decarbonylation, and therefore does not support dehydration of the C19 aldehyde prior to the final catalytic step. Ab initio molecular dynamics on the confirmed that the 1beta-hydrogen atom abstraction and deformylation or decarbonylation occur in a non-synchronous, coordinated manner. These calculations support a dehydrogenase behavior of aromatase in the final catalytic step, which can be summarized by 1beta-hydrogen atom abstraction followed by gem-diol deprotonation. Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. There are several classes of natural products that exert potent activities in aromatase inhibition, with the flavonoids being most prominent. Previous studies have exploited flavone and flavanone scaffolds for the development of new aromatase inhibitors. In this dissertation, we describe design, synthesis, and biological evaluation of a novel series of 2-(4-pyridylmethyl)thioisoflavones as the first example of synthetic isoflavone-based aromatase inhibitors. The biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the P450 heme.
Download or read book Design Synthesis and Evaluation of Potential Non steroidal Aromatase Inhibitors written by Martin Eric King and published by . This book was released on 1993 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Novel Antiestrogens written by Rodrigo Mendoza Sánchez and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Breast cancer is the most common form of cancer in women in the Western world and the second most fatal after lung cancer. Estrogens play a crucial role in normal breast development, but also contribute to mammary tumorigenesis. Estrogen signaling is mediated by intracellular estrogen receptors (ER[alpha] and ER[beta]), with ER[alpha] being a common target in breast cancer therapeutics. Two classes of competitive estrogen inhibitors have been investigated and proved to be useful for breast cancer treatment: full antiestrogens (FAE's) and selective estrogen receptor modulators (SERM's). A novel platform, FORECASTER, was developed in the Moitessier laboratory with the aim of integrating computational, medicinal and combinatorial chemistry. The successful validation of FORECASTER as a computer-aided drug design platform is described. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries and to filter and extract a highly diverse library from the NCI database. The virtual screening of a diverse library seeded with known active compounds followed by a search for analogs yielded a high enrichment factor. Moreover, the virtual screening of a designed virtual combinatorial library that included known actives resulted in a highly discriminative process. The laboratory of Dr. Sylvie Mader at University of Montreal showed that only FAE's induce a strong and fast SUMOylation of ER[alpha] in a variety of cell lines, strongly suggesting that SUMOylation is a general property related to full antiestrogenicity. A collaboration between the Gleason and Mader laboratories resulted in an SAR study of ER[alpha] ligands with different side chain lengths that revealed a specific side chain length of 15 to 19 atoms was necessary to differentiate SERM's from FAE's through the induction of SUMOylation. Histone deacetylase inhibitors (HDACi's) have emerged as a new and growing class of anticancer agents. Recent findings have shown that co-treatment of SERM's or FAE's with HDACi's can significantly decrease the growth of breast cancer cells. Inspired by the success of the vitamin D/HDACi hybrids developed within our group, and taking advantage of structural features of both kinds of molecules, we developed a new family of antiestrogen/HDACi hybrids. A first generation set of hybrids were designed by replacing the tertiary amide of FAE ICI-164,384 with three different zinc binding groups: hydroxamic acid, o-aminoanilide and N-butylhydroxamate. Both the hydroxamic acid and the o-aminoanilide hybrids displayed both antiestrogenic and HDAC inhibitory activities whereas N-butylhydroxamate hybrid displayed antiestrogenic activity but a poor HDAC inhibition profile. All hybrids inhibited MCF-7 cell proliferation and validated the proof of concept regarding the formation of this class of hybrids. However, none of the hybrids showed an improved profile compared to known antiestrogens or HDACi's. A second generation set of hybrids exploiting the same zinc binding groups with SERM- and FAE-like side chains were developed in an effort to balance the activity of our hybrids. Hydroxamic acids showed a consistent inhibition of HDAC's while displaying poor antiestrogenic activity in most cases. Ortho-amino anilides showed modest HDAC inhibition activity and only aliphatic-based o-amino-anilides behaved as antiestrogens. N-Butyl-hydroxamates showed a reduced potency to inhibit HDAC's compared to their hydroxamic acid counterparts but retained antiestrogenic behaviour. Overall, our second-generation hybrids did not show equal or improved HDAC inhibition and antiestrogenic activities relative to known antiestrogens and HDACi's. " --
Download or read book The Design Synthesis and Biological Evaluation of Novel Antitumor Agents written by Jude E. Mathews and published by . This book was released on 1996 with total page 354 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Novel PBD Heterocycle and Conjugates as Potntial Transcription Factor Binding Inhibitors written by Rachel Marina Hawkins and published by . This book was released on 2007 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis Biological Evaluation of Novel Het Aromatic Aromatic Analogs for the Treatment of HIV Cancer Cognitive Dysfunctions written by Mohit Gupta and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Selective Estrogen Receptor Modulator histone Deacetylase Inhibitor Hybrid Molecules written by Anthony Palermo and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Therapeutic options for the treatment of breast cancer have long been limited to invasive surgical procedures, or chemo- and radiotherapies that are plagued with detrimental side-effects. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are a large subclass of molecules that have been used in adjuvant therapies and have provided substantial clinical benefits as preventative and long-term treatment options. Despite their success, endocrine therapies face several challenges including the development of endocrine resistance and, in the case of tamoxifen, the increased risk of endometrial cancer. Recent studies have shown that dual administration of SERMS and histone deacetylase inhibitors (HDACis) in vitro have led to cooperative effects such as increased drug potency, the resensitization of endocrine resistant cell lines, and an overall decrease in the risk of endometrial cancer development. In an effort to combine the cooperative effects of SERMs and HDACis, this project focuses on the design, synthesis, and biological evaluation of a series of hybrid SERM/HDACi molecules that combine the pharmacophores of both drug classes.The design of the hybrids was based on previous research projects investigating hybrid antiestrogens within the Gleason group. This project expanded on a promising subsetof 4-OHT based hybrids and began with in silico screening of a virtual library using the FORECASTOR docking platform. Seven compounds were chosen for synthesis and a previously devised route was unsuccessfully attempted using a McMurry cross-coupling as the key step. An alternate route to the triphenylethylene scaffold is hinged on a highly convergent and modular three-component coupling reaction was designed and successfully carried out. Four hybrids were synthesized and purified by preparatory HPLC prior to biological evaluation.Fluorogenic HDACi assays to determine the hybrid affinities of HDACs 3 and 6 were carried out by the author within the Gleason lab. Three of the four hybrids showed lowmicromolar HDAC 3 potencies (IC50) and the fourth showed submicromolar potency, and suggested that increased chain-lengths led to a higher degree of HDAC inhibition. HDAC 6 inhibition results trended similar to those of HDAC 3 and three of the four hybrids showed submicromolar potencies. Cell-based bioluminescence resonance energy transfer (BRET) and luciferase transactivation assays were conducted by the Mader lab at Université de Montréal to evaluate the ER affinity and antagonism profile of the hybrids. Each hybrid exhibited full antagonism against the ER and three of the hybrids showed submicromolar IC50 values with regards to their ER affinity. MCF-7 breast cancer cell growth curves were carried out and a single hybrid outperformed 4-hydroxytamoxifen (4-OHT), tamoxifen, and endoxifen. The ER data alongside the HDACi results are suggestive of a hybrid SERM/HDACi that was capable of eliciting a cooperative antiproliferative effect against the breast cancer cell line.The final chapter of this thesis presents a brief project regarding the design of a 3-acyl-1,5-diene substrate for the organocatalytic Cope rearrangement. A novel diazepanecarboxylate organocatalyst capable of catalyzing the Cope rearrangement of hindered aldehydes via iminium catalysis was recently reported by the Gleason group. DFT calculations suggested that iminium ion formation of 3-acyl-1,5-dienes would accelerate the Cope rearrangement. The final 3-acyl-1,5-diene substrate was shown to be capable of undergoing the Cope rearrangement under simple thermal conditions and future work will investigate the potential for organocatalytic rate acceleration." --
Download or read book The Design Synthesis and Biological Evaluation of Novel Barbiturate based MMP Inhibitors written by Jun Wang and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structure based Design Synthesis and Biological Evaluation of Novel O N acetylglucosaminyltransferase Inhibitors written by Elena Maria Loi and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Selective Estrogen Receptor Modulator histone Deacetylase Inhibitor Hybrid Drug Molecules written by Yufei Wang and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The prognosis for those diagnosed with breast cancer has dramatically improved since the 1980’s, primarily due to improved diagnostic and treatment methods. One such treatment is a class of drugs called selective estrogen receptor modulators (SERMs). SERMs are a popular treatment option for breast cancer, commonly employed as adjuvant therapy. Prototypical examples of SERMs are tamoxifen and raloxifene. Despite their widespread success, breast cancers can often develop resistance to SERMs. As a result, other biological targets which may mitigate this resistance have been identified. Recent interest in the field has arisen around histone deacetylases (HDACs), which are a class of enzymes that have been implicated in promoting resistance in breast carcinoma. Studies have demonstrated the combination treatment of SERMs and HDAC inhibitors (HDACi’s) elicits a cooperative effect in enhancing cytotoxicity and resensitizing resistant breast cancers. In an effort to maximize the cooperative effects of SERMs and HDACi’s, the project detailed in this thesis describes the design, synthesis, and biological evaluation of a series of hybrid raloxifene/HDACi molecules that combine the pharmacophores of both drug classes. Previous work by the Gleason laboratory found tamoxifen/HDACi hybrids to exhibit potent biological activity, but further exploration of these would be laborious due to their inherent instability. As a result, a synthesis of raloxifene/HDACi hybrids was developed. Significant synthetic challenges resulted from the comparatively electron-deficient nature of key intermediates, making known methods used for raloxifene inapplicable towards these targets. After notable route scouting and reaction optimization, these challenges were resolved and a small library of seven hybrid drug molecules were successfully synthesized and purified prior to biological evaluation. Fluorogenic HDACi assays determined the IC50 values of the raloxifene/HDACi hybrids against HDAC1 and HDAC6. All hybrids demonstrated sub-micromolar IC50 values for HDAC1. For HDAC6, one hybrid showed low micromolar potency for HDAC6, while all others had sub-micromolar values. Generally, carbon-linked hybrids were more potent than oxygen-linked hybrids against HDAC1, while the reverse was true for HDAC6.Preliminary biological assays performed by the Mader lab at the Université de Montréal demonstrate all hybrids antagonize the ER at a low micromolar dose, both in the presence and in the absence of E2. A more conclusive result of the SERM/HDACi hybrids can be drawn once further biological testing has been completed by the Mader lab"--
Download or read book Design Synthesis and Biological Evaluation of Novel PBD heterocycle Conjugates as Potential Transcription Factor Binding Inhibitors written by and published by . This book was released on 2007 with total page 476 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Novel and Selective Inhibitors of Enzymes of the Endocannabinoid System written by Samuele Maramai and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Design Synthesis and Biological Evaluation of Novel Poly ADP ribose polymerase 1 PARP 1 Inhibitors written by Maulik R. Patel and published by . This book was released on 2012 with total page 258 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book A Comprehensive Guide to the Therapeutic Use of Aminoglutethimide written by Richard J. Santen and published by S. Karger AG (Switzerland). This book was released on 1982 with total page 176 pages. Available in PDF, EPUB and Kindle. Book excerpt:
