Affinity Modification — Organic Chemistry
Dmitri G. Knorre, Valentin V. Vlassov in Affinity Modification of Biopolymers, 1989
It should be noted that detailed mechanisms of many of the reactions which are considered as suicide inhibition due to the formation of reactive species by the enzymes remain to be investigated. The described mechanisms of formation of reactive species are in many cases hypothetical since experimental studies of the very short-living intermediates and structural analysis of the modified enzymes are related to considerable difficulties. First, detailed chemical and physicochemical studies of enzymes modified with substrate analogues have demonstrated that in some cases where the usual paradigm could suggest suicidal inhibition through the formation of highly reactive intermediate species; in fact, the usual affinity modification takes place. Thus, irreversible inhibitors of chymotrypsin, derivatives of 6- chloro-2-pyrone, can be thought to be converted to highly reactive acyl chlorides upon enzymatic lactone hydrolysis and acyl enzyme formation.
Radiolabeled Enzyme Inhibitors
William C. Eckelman, Lelio G. Colombetti in Receptor-Binding Radiotracers, 2019
The requirements for a successful suicide inhibitor are It must be a substrate for the target enzyme. The closer the inhibitor resembles the natural substrate, the more likely the inhibitor will workIt must be converted from a chemically inactive compound to a chemically reactive compound by the target enzymeThe reactive group must be generated within bonding distance of a nucleophilic residue in the enzyme’s active siteThe rate of covalent attachment of the inhibitor to the active site must be faster than the rate of dissociation of the enzyme-inhibitor complex
Endocrine Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Exemestane works by acting as a false substrate for the aromatase enzyme. Due to its structural similarity to the enzyme’s natural substrates, it binds permanently and irreversibly (i.e., covalently) to the active site of the enzyme (a process known as “suicide inhibition”), thus preventing the conversion of androgen into estrogen. Although the precise mechanism of this irreversible binding has not been fully elucidated, several plausible mechanisms have been proposed. For example, exemestane already contains an electrophilic center, and so could react directly with a nucleophilic group within the active site of the enzyme without further activation. The electrophilic methylidene group at its 6-position, which is conjugated through the 4,5-double bond to the C3-carbonyl group, is set up for a Michael Addition reaction from a nucleophilic group within the active site of the enzyme (Figure 8.17). An alternative suggestion is that exemestane initially binds to the substrate-binding site of the enzyme through Van der Waals forces (e.g., from residues I133 and F134 within the B′-C loop), with hydrogen bonds forming between residue S478 and the C3-carbonyl group of exemestane. The molecule may then be converted to electrophilic reactive intermediates by heme through hydroxylation at the C19-position followed by irreversible binding of these intermediates to the enzyme possibly through the D309 residue.
Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers
Published in Expert Opinion on Drug Discovery, 2019
Angelo Spinello, Ida Ritacco, Alessandra Magistrato
A milestone in the rational structure-based design of AIs was the release of HA crystal structure in complex with ASD at 2.9 Å resolution (pdb ID 3EQM) [74]. This structure confirmed the key importance of several active site residues, such as Asp309, Thr310, Met374 and Ser478 for catalysis and substrate recognition. Other X-ray structures have been deposited in the protein data bank by the same authors in subsequent years, such as a refinement of the ASD/HA complex (pdb ID 3S97) [55], and, more recently, HA in complex with TST, which share the same interactions patterns of ASD with the catalytic site [92]. These authors also trapped in the crystal the steroidal AI EXE (pdb ID 3S7S) [55]. As expected, this third-generation inhibitor possesses an almost identical binding pose to the endogenous substrate ASD, establishing hydrogen bonds with Asp309 and the backbone of Met347. Although EXE was reported to act as a suicide inhibitor, binding covalently to the catalytic site, its crystal structure in complex with HA did not reveal any covalent bond between the drug and HA probably due to the absence of the CPR, in the crystallization medium, which must provide the electron necessary for the reaction.
Coumarin carbonic anhydrase inhibitors from natural sources
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Claudiu T. Supuran
Apart from their highly interesting features as isoform-selective inhibitors, the discovery of coumarins as CAIs stimulated the research for the discovery of new chemotypes possessing such properties or similar inhibition mechanisms. Indeed, the monocyclic 5- and 6-ring lactones and thiolactones were reported to possess CA inhibitory effects71, as well as thio- and 2-thioxo-coumarins72, quinoline-2-ones73, sulfocoumarins74, homosulfocoumarins75,76 and various hetero-coumarins incorporating selenium, tellurium and other elements77. More recently, this type of prodrug CAI inspired also other groups to investigate this type of suicide inhibitor, such as for example aspirin, reported by McKenna’s group78. The huge number of synthetic studies of non-NP coumarins which have been reported in the last decade are not mentioned here, but many such compounds have been designed and showed a relevant biological activity. Overall, the very interesting moieties present in the NP coumarins make them a source of inspiration for medicinal chemists and pharmacologists in the search of new drugs with a safer profile and specific action in a variety of disorders, starting from the infective ones79 and ending with tumours80 and inflammatory diseases81. For the moment, only the human α-CAs were investigated for their inhibition profile with coumarins, but such enzymes are also present in other organisms, such as pathogenic bacteria, protozoans, and fungi82–85. Investigation of coumarin derivatives (including NPCs) against these enzymes may thus lead to interesting developments in the fight of infections produced by such pathogens.
QbD-assisted development of lipidic nanocapsules for antiestrogenic activity of exemestane in breast cancer
Published in Journal of Liposome Research, 2023
Priya Singh, Priyanka Maurya, Raquibun Nisha, Neelu Singh, Poonam Parashar, Nidhi Mishra, Ravi Raj Pal, Shubhini A. Saraf
Breast malignancy is common among Indian women, with a prevalence of 26.8 in a hundred thousand females and considerable morbidity (Malvia et al.2017). In the United States, 3,25 130 instances of the disease have been detected in women by 2020 (Shumway et al. 2020). Breast cancer is identified in 64% of cases at a localized stage, with a 5-year survival rate of 99%. Approximately 16% of mortality is attributed to an imbalance in hormones which leads to disease progression (Singh et al.2019). Exemestane (Exe) is a steroidal irreversible aromatase inhibitor (AI) commonly used to treat breast cancer. It causes suicide inhibition, or the irreversible binding of a false substrate to the aromatase enzyme and inactivating the enzyme. Because Exe primarily targets the aromatase enzyme, which only functions in the rate-limiting phase of estrogen synthesis, it has no impact on other adrenal hormones (Mokhtar et al. 2022). Aromatase is an enzyme that produces estrogen; when Exe is taken, it prevents estrogen synthesis. As a result, the level of estrogen will decrease and the formation of malignant cells will be slowed down. Chemically Aromasin, also known as Exe (6-methylenandrosta-1,4-diene-3,17-dione), was used as an oral aromatase inhibitor. Exe is a lipophilic molecule that is soluble in organic solvents like methanol and N,N-dimethylformamide (Mohanty et al. 2022). It is recognized as a first-line therapy for hormone-dependent breast cancer. Its structure is similar to that of naturally occurring androstenedione in the body. Thus, the primary enzyme (aromatase) that converts androgen to estrogen, is the primary target for treating breast cancer. Therefore, this is a targeted and effective treatment for women with estrogen-receptor-positive (ER+) breast cancer (Ingle 2002, Russo and Russo 2006).
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