Cysteine cathepsins (CTS), being involved in both physiological and pathological processes, play an important role in the human body. During the last 30 years, it has been shown that CTS are highly ...upregulated in a wide variety of cancer types although they have received a little attention as a potential therapeutic target as compared to serine or metalloproteinases. Studies on the increasing problem of neoplastic progression have revealed that secretion of cell-surface- and intracellular cysteine proteases is aberrant in tumor cells and has an impact on their growth, invasion, and metastasis by taking part in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. Considering the role of CTS in carcinogenesis, inhibition of these enzymes becomes an attractive strategy for cancer therapy. The downregulation of natural CTS inhibitors (CTSsis), such as cystatins, observed in various types of cancer, supports this claim. The intention of this review is to highlight the relationship of CTS with cancer and to present illustrations that explain how some of their inhibitors affect processes related to neoplastic progression.
Cysteine cathepsins (CTS) are involved in tumor development and metastasis. Hence, cysteine cathepsin inhibitors are considered to constitute promising therapeutics in cancer treatment. Display omitted
•Cysteine cathepsins (CTS) are highly upregulated in various types of cancer.•Inhibition of CTS becomes an attractive strategy for cancer therapy.•Cystatins, endogenous CTS inhibitors, may control tumor progression.•Exogenous inhibitors of cysteine cathepsins are a lead for new anticancer drugs.
A series of novel 3-/2,3-substituted pyrido4,3-e1,2,4triazino3,2-c1,2,4thiadiazine 6,6-dioxides 4-28 have been synthesized by the reaction of ...3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate anticancer activity toward human cancer cell lines, HCT-116, MCF-7 and HeLa. The structure of this novel heterocyclic ring system was confirmed by ¹D-NMR and ²D-NMR spectroscopic data including COSY, ROESY and HMBC, elemental analyses and MS spectrometry.
A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27-60 have been synthesized by the reaction of aminoguanidines with an ...appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC50 values below 100 μM. It was found that for the analogues 36-38 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R² and Ar = 4-CF₃-C₆H₄ moiety in 2-(R²-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC50 = 36 μM), HeLa (IC50 = 34 μM) cell lines, apoptosis-inducing activity and moderate metabolic stability.
In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great ...flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logk
w
) and inhibitory activity (logK
i
) were used as drug properties. Genetic algorithm-partial least squares (GA-PLS) provided a QSPR model with high prediction capability employing only seven molecular descriptors. As a proof-of-concept, optimal drug structure was obtained by inverting the model with respect to reference drug properties. 3509 ligands were ranked accordingly. Top 10 ligands were further validated through molecular docking. Large-scale MD simulations were performed to test the stability of structures of selected ligands obtained through docking complemented with biophysical experiments.
A series of novel 2-alkythio-4-chloro-
-imino-(heteroaryl)methylbenzenesulfonamide derivatives,
-
, were synthesized in the reaction of the
-(benzenesulfonyl)cyanamide potassium salts
-
with the ...appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds,
-
, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC
: 6-7 μM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC
: 18-20 μM). It was found that the anti-proliferative effects of
,
and
were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t
for
-
in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.
A series of novel 2-(4-amino-6-R
-1,3,5-triazin-2-yl)methylthio-4-chloro-5-methyl-
-(5-R
-
-benzo
imidazol-2(
)-ylidene)benzenesulfonamides
-
was synthesized by the reaction of 5-substituted ethyl ...2-{5-R
-2-
-(5-chloro-
-benzo
imidazol-2(
)-ylidene)sulfamoyl-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds,
and
, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC
: 7-11 µM; 15-24 µM and 11-18 µM), respectively. Further QSAR (Quantitative Structure-Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds,
and
, within the active site of the MDM2 protein.
A series of novel N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9–41 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic ...anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed KI in the range of 87–6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7–416 nM and against hCA XII at range of 0.96–540 nM. Compounds 10, 12–14, 16, 18–20, 24–26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (KI = 4.7–21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (KI = 24–50 nM). Compound 14 was the most potent inhibitor of hCA I (KI = 87 nM), hCA IX (KI = 4.7 nM) and hCA XII (KI = 0.96 nM), while 26 was the most effective inhibitor of hCA II (KI = 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX = 261) and hCA II (hCA II/hCA IX = 26). The in vitro antitumor activity of compounds 10, 13, 14, 21, 22, 25, 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32–35 human tumor cell lines with GI50 in the range of 2.1–5.0 μM also showed relatively high inhibitory activity toward hCA IX and XII with KI from 18 to 40 nM.
A series of novel N-substituted N′-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines have been synthesized. Some of them exhibited a powerful carbonic anhydrase CAI, CAII, CAIX and CAXII inhibitory potency as well as anticancer activity. Display omitted
•Series of novel guanidines containing primary sulfonamide residue was synthesized.•The inhibitory activity against hCA I, II, IX and XII was investigated.•Thirteen compounds were stronger hCA IX inhibitors than clinically used sulfonamides.•Selectivity ratios CA IX versus CA II (≤26) was higher than reference (≤0.8).•Some compounds suppress growth of tumor cells in vitro.
Rising resistance of pathogenic bacteria reduces the options of treating hospital and non-hospital bacterial infections. There is a need to search for newer chemotherapies that will show ...antimicrobial ability against planktonic cells as well as bacterial biofilms. We have synthesized a series of
-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)amides, namely, molecular hybrids, which include a 2-mercaptobenzenosulfonamide fragment and either cinnamic or cyclohexylpropionic acid residues. The antimicrobial activity of compounds
‒
was evaluated on Gram-positive, Gram-negative bacteria and fungal species. Experiments took into account investigation of antibacterial activity against planktonic cells as well as biofilms. Compounds
‒
showed high bacteriostatic activity against staphylococci, with the most active molecules
and
presenting low MIC values of 4-8 μg/mL against reference methicillin-resistant
(MRSA) and methicillin-sensitive
(MSSA) strains as well as clinical isolates. Compounds
and
also showed an ability to inhibit biofilms formed by MRSA and MSSA. The potential of
and
as antibiofilm agents was supported by cytotoxicity assays that indicated no cytotoxic effect either on normal cells of human keratinocytes or on human cancer cells, including cervical, colon, and breast cancer lines.
Sulfonamides are a classic group of chemotherapeutic drugs with a broad spectrum of pharmacological action, including anticancer activity. In this work, reversed-phase high-performance liquid ...chromatography and biomimetic chromatography were applied to characterize the lipophilicity of sulfonamide derivatives with proven anticancer activities against human colon cancer. Chromatographically determined lipophilicity parameters were compared with obtained logP, employing various computational approaches. Similarities and dissimilarities between experimental and computational logP were studied using principal component analysis, cluster analysis, and the sum of ranking differences. Furthermore, quantitative structure–retention relationship modeling was applied to understand the influences of sulfonamide’s molecular properties on lipophilicity and affinity to phospholipids.
In the search for new compounds with antitumor activity, new potential anticancer agents were designed as molecular hybrids containing the structures of a triazine ring and a sulfonamide fragment. ...Applying the synthesis in solution, a base of new sulfonamide derivatives 20–162 was obtained by the reaction of the corresponding esters 11–19 with appropriate biguanide hydrochlorides. The structures of the compounds were confirmed by spectroscopy (IR, NMR), mass spectrometry (HRMS or MALDI-TOF/TOF), elemental analysis (C,H,N) and X-ray crystallography. The cytotoxic activity of the obtained compounds toward three tumor cell lines, HCT-116, MCF-7 and HeLa, was examined. The results showed that some of the most active compounds belonged to the R1 = 4-trifluoromethylbenzyl and R1 = 3,5-bis(trifluoromethyl)benzyl series and exhibited IC50 values ranging from 3.6 µM to 11.0 µM. The SAR relationships were described, indicating the key role of the R2 = 4-phenylpiperazin-1-yl substituent for the cytotoxic activity against the HCT-116 and MCF-7 lines. The studies regarding the mechanism of action of the active compounds included the assessment of the inhibition of MDM2-p53 interactions, cell cycle analysis and apoptosis induction examination. The results indicated that the studied compounds did not inhibit MDM2-p53 interactions but induced G0/G1 and G2/M cell cycle arrest in a p53-independent manner. Furthermore, the active compounds induced apoptosis in cells harboring wild-type and mutant p53. The compound design was conducted step by step and assisted by QSAR models that correlated the activity of the compounds against the HCT-116 cell line with molecular descriptors.
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