β-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: Part 2. Optimization of α-amino substituents

Yang, Shyh‐Ming; Scannevin, Robert H.; Wang, Bingbing; Burke, Sharon L.; Huang, Zhihong; Karnachi, Prabha; Wilson, Lawrence J.; Rhodes, Kenneth J.; Lagu, Bharat; Murray, William V.

doi:10.1016/j.bmcl.2007.11.129

Cited by 22 publications

(9 citation statements)

References 27 publications

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“…This modification leads to new MMP-2/MMP-9 inhibitors characterized by improved inhibitory activities and ADME properties. In particular, compounds containing the α-cyclic amino group showed low protein binding, good water solubility, and enhanced pharmacokinetic properties [46].…”

Section: Inhibition Of Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

et al. 2020

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Zinc (II) is an important biometal in human physiology. Moreover, in the last two decades, it was deeply studied for its involvement in several pathological states. In particular, the regulation of its concentration in synaptic clefts can be fundamental for the treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Zinc (II) is also a constituent of metalloenzymes (i.e., matrix metalloproteinases, MMPs, and carbonic anhydrases, CAs) with catalytic function; therefore, it can be an important target for the inhibition of these proteins, frequently involved in cancer onset. This review is focused on the significance of zinc (II) chelating agents in past and future medicinal chemistry research, and on the importance of selectivity in order to revamp the possibility of their use in therapy, often hindered by possible side effects.

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Section: Inhibition Of Matrix Metalloproteinasesmentioning

confidence: 99%

Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

et al. 2020

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“…1) were reported. 36,37 This shift further maintains satisfactory inhibitory activities for both MMP-2 and MMP-9.…”

Section: Introductionmentioning

confidence: 75%

A combined molecular modeling study on gelatinases and their potent inhibitors

et al. 2009

J Comput Chem

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Zinc-dependent matrix metalloproteinase (MMP) family is considered to be an attractive target because of its important role in many physiological and pathological processes. In the present work, a molecular modeling study combining protein-, ligand- and complex-based computational methods was performed to analyze a new series of beta-N-biaryl ether sulfonamide hydroxamates as potent inhibitors of gelatinase A (MMP-2) and gelatinase B (MMP-9). Firstly, the similarities and differences between the binding sites of MMP-2 and MMP-9 were analyzed through sequence alignment and structural superimposition. Secondly, in order to extract structural features influencing the activities of these inhibitors, quantitative structure-activity relationship (QSAR) models using genetic algorithm-multiple linear regression (GA-MLR), comparative molecular field (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed. The proposed QSAR models could give good predictive ability for the studied inhibitors. Thirdly, docking study was employed to further explore the binding mode between the ligand and protein. The results from all the above analyses could provide the information about the similarities and differences of the binding mode between the MMP-2, MMP-9 and their potent inhibitors. The obtained results can provide very useful information for the design of new potential inhibitors.

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“…As it was mentioned before, this chemical class is large and has provided potent MMPIs. Recently, a series of -N-biaryl ether sulfonamide hydroxamates has been reported as novel potent gelatinase inhibitors (Tables 15-18) [124,125]. Structure-activity relationship studies suggested that the methanesulfonyl group together with -N-biaryl ether type P1' moiety is the optimal combination to obtain low nanomolar activities against gelatinases.…”

Section: N-sulfonyl-2-aminoacetic Hydroxamates and N-sulfonyl-3-aminomentioning

confidence: 99%

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

Serra

Bruczko²,

Zapico³

et al. 2012

CMC

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Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.

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β-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: Part 2. Optimization of α-amino substituents

Cited by 22 publications

References 27 publications

Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

A combined molecular modeling study on gelatinases and their potent inhibitors

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

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