New 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-N-(imidazolidin-2-ylidene)-4-chloro-5-methylbenzenesulfonamide Derivatives, Design, Synthesis and Anticancer Evaluation.

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.

Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure-Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(1H-benzo[d]imidazol-2(3H)-ylidene)Benzenesulfonamides.

A series of novel 2-[(4-amino-6-R2-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(5-R1-1H-benzo[d]imidazol-2(3H)-ylidene)benzenesulfonamides 6-49 was synthesized by the reaction of 5-substituted ethyl 2-{5-R1-2-[N-(5-chloro-1H-benzo[d]imidazol-2(3H)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, 22 and 46, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC50: 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, 22 and 46, within the active site of the MDM2 protein.

Synthesis, Anticancer Evaluation and Structure-Activity Analysis of Novel (E)- 5-(2-Arylvinyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamides.

To learn more about the structure-activity relationships of (E)-3-(5-styryl-1,3,4-oxadiazol-2-yl)benzenesulfonamide derivatives, which in our previous research displayed promising in vitro anticancer activity, we have synthesized a group of novel (E)-5-[(5-(2-arylvinyl)-1,3,4-oxadiazol-2-yl)]-4-chloro-2-R1-benzenesulfonamides 7-36 as well as (E)-4-[5-styryl1,3,4-oxadiazol-2-yl]benzenesulfonamides 47-50 and (E)-2-(2,4-dichlorophenyl)-5-(2-arylvinyl)-1,3,4-oxadiazols 51-55. All target derivatives were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. The obtained results were analyzed in order to explain the influence of a structure of the 2-aryl-vinyl substituent and benzenesulfonamide scaffold on the anti-tumor activity. Compound 31, bearing 5-nitrothiophene moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 0.5, 4, and 4.5 µM, respectively. Analysis of structure-activity relationship showed significant differences in activity depending on the substituent in position 3 of the benzenesulfonamide ring and indicated as the optimal meta position of the sulfonamide moiety relative to the oxadizole ring. In the next stage, chemometric analysis was performed basing on a set of computed molecular descriptors. Hierarchical cluster analysis was used to examine the internal structure of the obtained data and the quantitative structure-activity relationship (QSAR) analysis with multiple linear regression (MLR) method allowed for finding statistically significant models for predicting activity towards all three cancer cell lines.

Synthesis of 2-alkylthio-N-(quinazolin-2-yl)benzenesulfonamide derivatives: anticancer activity, QSAR studies, and metabolic stability.

ABSTRACT: A new series of 2-alkylthio-N-(quinazolin-2-yl)benzenesulfonamide derivatives have been synthesized and evaluated in vitro for their antiproliferative activity by MTT assay against cancer cell lines HCT-116, MCF-7, and HeLa as well as the NCI-60 human tumor cell lines screen. In NCI screen, three compounds inhibited approximately 50% growth of RPMI-8226 and A549/ATCC cell lines. The mean of IC50 calculated in MTT assays for three tested cell lines was about 45 µM for four compounds. The QSAR allowed finding statistically significant OPLS models for HeLa cell line. Metabolic stability in vitro studies indicated favorable and unfavorable structural elements. The good metabolic stability, with t1/2 higher than 40 min, was observed for three derivatives, which together with their antiproliferative activity and good ADMET profile, makes them good leading structures for further research.

Target-based drug discovery through inversion of quantitative structure-drug-property relationships and molecular simulation: CA IX-sulphonamide complexes.

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 (logkw) and inhibitory activity (logKi) 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.

Synthesis, molecular structure, and metabolic stability of new series of N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-1-(5-phenyl-1H-pyrazol-1-yl)amidine as potential anti-cancer agents.

A series of new N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-1-(5-phenyl-1H-pyrazol-1-yl)amidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The studied compounds display selective activity mainly against HCT-116 and HeLa cells. Thus, five compounds show selective cytotoxic effect against HCT-116 (IC50 = 3-10 µM) and HeLa (IC50 = 7 µM). Importantly, the noticed values of IC50 for four compounds are almost 4-fold lower for HeLa than non-malignant HaCaT cells. More-in-depth biological research revealed that the treatment of HCT-116 and HeLa with active compound resulted in increased numbers of cells in sub-G1 phase in a time dependent manner, while non-active derivative does not influence cell cycle. Metabolic stability assays using liver microsomes and NADPH provide important information on compounds susceptibility to phase 1 biotransformation reactions.

Novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(1,3,5-triazin-2-ylamino)guanidine derivatives: Inhibition of human carbonic anhydrase cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII, anticancer activity, and molecular modeling studies.

A series of novel 2-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)-1-(6-substituted-4-chloro-1,3,5-triazin-2-ylamino)guanidine derivatives 9-20 have been synthesized by substitution of chlorine atom at the 1,3,5-triazine ring in compounds 5-8 with 3- or 4-aminobenzenesulfonamide and 4-(aminomethyl)benzenesulfonamide hydrochloride. All the synthesized compounds were evaluated for their inhibitory activity toward hCA I, II, IX and XII as well as anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. The investigated compounds showed weak inhibitory potency against the human CA I, while activity toward hCA II was differentiated and depended on structure of inhibitor (KI: 5.4-933.1 nM). Compounds containing the 4-sulfamoylphenyl moiety (9-12) exhibited the strongest inhibitory activity against hCA IX with KI values from 37.1 to 42.9 nM, as well as against hCA XII in range of 31-91.9 nM. The most promising compound 12 (KI = 41 nM) showed the highest selectivity toward hCA IX versus hCA I (hCA I/hCA IX = 18) and hCA II (hCA II/hCA IX = 4). Compound 12 displayed prominent cytotoxic effect selectively toward HeLa cancer cells (IC50 = 17 µM) and did not exhibit toxicity to the non-cancerous HaCaT cells. In silico analysis suggested that despite the lack of a single binding pose, the selective affinity is conferred by specific interactions with an arginine moiety, as well as better-defined binding modes within the active site.

Inhibition studies of Brucella suis ß-carbonic anhydrases with a series of 4-substituted pyridine-3-sulphonamides.

The two ß-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Brucella suis, BsuCA1 and BsuCA2, were investigated for their inhibition profile with a series of pyridine-3-sulphonamide derivatives incorporating 4-hetaryl moieties. BsuCA1 was effectively inhibited by these sulphonamides with inhibition constants ranging between 34 and 624 nM. BsuCA2 was less sensitive to these inhibitors, with KIs in the range of 62 nM - > 10 µM. The nature of the 4-substituent present on the pyridine ring was the main factor influencing the inhibitory profile against both isoforms, with 4-halogenophenylpiperazin-1-yl and 3,4,5-trisubstituted-pyrazol-1-yl derivatives showing the most effective inhibition. Some of these sulphonamides were most effective bacterial CA than human (h) CA I and II inhibitors, making them selective for the prokaryotic enzymes. Investigation of bacterial CA inhibitors may be relevant for finding antibiotics with a new mechanism of action compared to the clinically used agents for which substantial drug resistance emerged.

Syntheses of Novel 4-Substituted N-(5-amino-1H-1,2,4-triazol-3-yl)pyridine-3-sulfonamide Derivatives with Potential Antifungal Activity.

Candidiasis represent a serious threat for patients with altered immune responses. Therefore, we have undertaken the synthesis of compounds comprising a pyridine-3-sulfonamide scaffold and known antifungally active 1,2,4-triazole substituents. Thus a series of novel 4-substituted N-(5-amino-1H-1,2,4-triazol-3-yl)pyridine-3-sulfonamides have been synthesized by multistep reactions starting from 4-chloropyridine-3-sulfonamide via N'-cyano-N-[(4-substitutedpyridin-3-yl)sulfonyl]carbamimidothioates which were further converted with hydrazine hydrate to the corresponding 1,2,4-triazole derivatives 26-36. The final compounds were evaluated for antifungal activity against strains of the genera Candida, Geotrichum, Rhodotorula, and Saccharomycess isolated from patients with mycosis. Many of them show greater efficacy than fluconazole, mostly towards Candida albicans and Rhodotorula mucilaginosa species, with MIC values ≤ 25 µg/mL. A docking study of the most active compounds 26, 34 and 35 was performed showing the potential mode of binding to Candida albicans lanosterol 14α-demethylase. Also in vitro cytotoxicity of selected compounds have been evaluated on the NCI-60 cell line panel.

Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents - Synthesis, molecular structure, QSAR studies and metabolic stability.

A series of new 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The obtained results indicated that these compounds display prominent cytotoxic effect. The best anticancer properties have been observed for derivatives 44 (IC50 = 6-18 µM) and 45 (IC50 = 8-14 µM). Very good results of antiproliferative assays have been also shown for compounds 26, 36, and 46 and noticeable anticancer profile has been found for set of derivatives 34-39. Based on results of MTT assays the structure-activity relationships have been drawn. More in-depth biological research revealed that compounds 26, 33, 37, 39, 41 and 43 display cytotoxic effect only against cancer cells and do not inhibit the growth of non-malignant HaCaT cells. Furthermore, the novel series of derivatives have shown good metabolic stability, especially among the pharmacologically active compounds. To obtain a deeper insight into the molecular description of compounds activity the QSAR studies have been applied. Support vector machines (SVM) have been used to developed QSAR models for predicting the anti-proliferative activity of novel derivatives. The obtained SVM models have shown prognostic ability for HCT-116 and HeLa cell lines and as a result these models may be useful for further development of structurally similar derivatives with better biological properties.

Novel 2-benzylthio-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides with anticancer activity: Synthesis, QSAR study, and metabolic stability.

A series of novel 2-benzylthio-4-chloro-5-(5-substituted 1,3,4-oxadiazol-2-yl)benzenesulfonamides (4-27) have been synthesized as potential anticancer agents. MTT assay was carried out to determine the cytotoxic activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa as well as to determine the influence on human keratinocyte cell line HaCaT. Relatively high (IC50: 7-17 µM) cytostatic activity and selectivity against HeLa cell line was found for compounds 6, 7, 9-11 and 16. While compounds 23-27 bearing styryl moieties attached to a 1,3,4-oxadiazole ring at position 5, exhibited significant activity against two and/or three cancer cell lines with IC50: 11-29 µM. Further quantitative structure-activity relationships based on molecular descriptors calculated by DRAGON software, were investigated by Orthogonal Projections to Latent Structures (OPLS) technique and Variable Influence on Projection (VIP) analysis. Considering molecular descriptors with the highest influence on projection (highest VIP values) lipophilicity of tested compounds was pointed as main factor affecting activity towards HCT-116 cell line, while structural parameters associated with presence of styryl substituent in position 5 of 1,3,4-oxadiazole ring were identified as essential for activity towards MCF-7 breast cancer. In vitro tests for metabolic stability in the presences of pooled human liver microsomes and NADPH showed that some of the most active compounds 26 and 27 presented favorable metabolic stability with t1/2 in the range of 28.1-36.0 min.

Synthesis, QSAR studies, and metabolic stability of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives as potential anticancer and apoptosis-inducing agents.

A series of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives 12-46 have been synthesized by the reaction of aminoguanidines with an appropriate alpha-oxo-acids hydrates in glacial acetic acid. All the synthesized compounds were evaluated for their anticancer activity against HeLa, HCT-116, and MCF-7 human tumor cell lines. Two compounds 33 and 34 displayed outstanding cytotoxic effect selectively toward HeLa cancer cells (IC50  = 19 µm) and did not exhibit toxicity to the non-cancerous HaCaT cells. QSAR analysis determined the most important parameters controlling cytotoxic activity of 5-oxo-1,2,4-triazines against HeLa cells. QSAR model showed five significant descriptors: HATS6s (GETAWAY descriptor), RDF125 m (radial distribution function), SpMax7_Bh(p) (Burden descriptor), SM3_G (3D matrix descriptor), and Hy (hydrophilic factor). The apoptotic potential of the most active compounds was thoroughly analyzed through various assays: cells' morphology, DNA fragmentation, mitochondrial potential disruption, and phosphatidylserine translocation. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH. Compound 34 was the most resistant for human metabolism (t1/2  = 38.5 min) and can be pointed as a hit compound for further investigations.

Novel 5-Substituted 2-(Aylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides: Synthesis, Molecular Structure, Anticancer Activity, Apoptosis-Inducing Activity and Metabolic Stability.

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.

Synthesis, Molecular Structure, Metabolic Stability and QSAR Studies of a Novel Series of Anticancer N-Acylbenzenesulfonamides.

A series of novel N-acyl-4-chloro-5-methyl-2-(R¹-methylthio)benzenesulfonamides 18-47 have been synthesized by the reaction of N-[4-chloro-5-methyl-2-(R¹-methylthio) benzenesulfonyl]cyanamide potassium salts with appropriate carboxylic acids. Some of them showed anticancer activity toward the human cancer cell lines MCF-7, HCT-116 and HeLa, with the growth percentages (GPs) in the range from 7% to 46%. Quantitative structure-activity relationship (QSAR) studies on the cytotoxic activity of N-acylsulfonamides toward MCF-7, HCT-116 and HeLa were performed by using topological, ring and charge descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies revealed three predictive and statistically significant models for the investigated compounds. The results obtained with these models indicated that the anticancer activity of N-acylsulfonamides depends on topological distances, number of ring system, maximum positive charge and number of atom-centered fragments. The metabolic stability of the selected compounds had been evaluated on pooled human liver microsomes and NADPH, both R¹ and R² substituents of the N-acylsulfonamides simultaneously affected them.

Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity.

A series of novel 4-substituted-N-(phenylcarbamoyl)-3-pyridinesulfonamides 11-27 have been synthesized by the reaction of 4-substituted pyridine-3-sulfonamides 2-10 with the appropriate aryl isocyanates in presence of potassium carbonate. The in vitro anticancer activity of compounds 11, 12, 14-21 and 24-26 was evaluated at the U.S. National Cancer Institute and in light of the results, some structure-activity relationships were discussed. The most prominent compound, N-[(4-chlorophenyl)carbamoyl]-4-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyridine-3-sulfonamide (21) has exhibited a good activity profile and selectivity toward the subpanels of leukemia, colon cancer and melanoma, with average GI50 values ranging from 13.6 to 14.9 µM.

Synthesis of a new series of N4-substituted 4-(2-aminoethyl)benzenesulfonamides and their inhibitory effect on human carbonic anhydrase cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII.

A series of novel N(4)-substituted 4-(2-aminoethyl)benzenesulfonamides 5-17 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 tumor-associated isozymes CA IX and XII. Against the human CA I investigated compounds displayed KI values from 96.3 to 3520 nM, toward hCA II at range of 18.1-2055 nM, while against hCA IX ranging from 5.9 to 419 nM and against hCA XII in the range of 4.0-414 nM. The very good inhibitory activity against tumor-associated hCA IX and hCA XII was found. The six new compounds displayed a powerful inhibitory potency toward hCA IX (K(I) = 5.9-10.7 nM) in comparison with the clinically used CAIs AAZ, MZA, EZA, DCP and IND (24-50 nM). The most potent hCA IX and hCA XII inhibitors 11 and 12 (K(I): 5.9 and 6.2 nM for hCA IX and 4.3 and 4.0 nM for hCA XII, respectively) belonged to the compounds with cationic character and presented meaningful affinity to the transmembrane isoforms hCA IX and XII than to physiologically dominant isozymes hCA I and II with the selectivity ratios hCA IX versus hCA II and hCA XII versus hCA II for 11 and 12 in the range of 10-15.

Carbonic anhydrase inhibitors. Synthesis of heterocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII.

A series of novel heterocyclic 4-substituted pyridine-3-sulfonamides 2-13, 15-20 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 tumor-associated isozymes CA IX and XII. Against the human isozymes hCA I the new compounds showed K(I) values in the range 169-5400 nM, toward hCA II in range 58.5-1238 nM, against hCA IX in range 19.5-652 nM and against hCA XII in the range of 16.8-768 nM. Compounds 15-19 representing 4-(1H-pyrazol-1-yl)-3-pyridinesulfonamide derivatives showed good hCA IX inhibitory efficacy with K(I) = 19.5-48.6 nM comparable or more effective than clinically used sulfonamides: AAZ, MZA, EZA, DCP, IND (K(I) = 24-50 nM). Anticancer evaluation at a single dose 10 µM, against a panel of 60 human tumor cell lines, was performed at the US National Cancer Institute, on compounds 2, 3, 5-13, 16, 17, 19, 20. Among them 6 bearing 4-(3,4,-dichlorophenyl)piperazine moiety showed broad spectrum of growth inhibition in the range 25-89% over 26 cell lines representing all tumors subpanels.

Analysis of hemodynamics of intracranial saccular aneurysms.

The aim of this paper is to present the impact of artery curvature and neck size of aneurysms on growth rate and effectiveness of treatment of aneurysms. The dynamics of three-dimensional (3D) lateral aneurysms on arteries of different curvature were analysed using Comsol Femlab software. The simulations were performed for both steady as pulsatile flows. The effect of artery curvature and neck size of aneurysms on parameters such as flow velocity, aneurysm wall shear stress, size of the area of blood reaction (impact area) during the cardiac cycle were evaluated as well as relations between the size of impact area and artery curvature or neck size of aneurysms were provided.