A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants.

BACKGROUND: Better tools for post-chemotherapy amenorrhea risk assessment are needed for fertility preservation decision-making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post-chemotherapy in women with breast cancer. METHODS: 142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline-Cyclophosphamide-based (AC-based) or Cyclophosphamide-Methotrexate +5-Fluorouracil regimen. Pre- and/or post-chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6-18 months. RESULTS: In multivariable-adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post-chemotherapy was predictive of amenorrhea with <18 month follow-up. In longitudinal analysis estimating time trends, baseline AMH and gBRCApv status was associated with the risk of amenorrhea over 6-18 months; the AMH >2.0 ng/mL group showed attenuated time-trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86-0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04-1.20, p = 0.003). CONCLUSIONS: In addition to the pre- and post-treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post-chemotherapy.

Antiproliferative and Antiprostate Cancer Activities of Heterocyclic Compounds Derived from Cyclohexane-1,4-dione.

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicity of the synthesized compounds was studied on six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work.

Anti-proliferative, c-Met Inhibitions, and PAINS Evaluations of New Thiophene, Thiazole, Coumarin, Pyran, and Pyridine Derivatives.

BACKGROUND: 1,3-Diones are versatile reagents used for many heterocyclic transformations. Among such groups of compounds, cyclohexane-1,3-dione is widely used in organic synthesis to produce biologically active compounds. OBJECTIVE: In this work, target molecules were synthesized from tetrahydrobenzo[b]thiophen-3- carboxamide derivative with different substituents, and their structure-activity relationships were discussed in detail. METHODS: Cyclohexane-1,3-dione underwent different multi-component reactions to produce fused thiophene, thiazole, coumarin, pyran, and pyridine derivatives. The anti-proliferative activity of the newly synthesized compounds toward the six cancer cell lines, namely A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721 was studied. In addition, inhibitions of the most active compounds toward cancer cell lines classified according to the disease were also studied. Furthermore, Pan Assay Interference compounds (PAINS) of the selected compounds were analyzed, along with the c- Met inhibitions. RESULTS: Anti-proliferative evaluations were performed for all of the synthesized compounds, in which the varieties of substituents through the aryl ring and the heterocyclic ring afforded compounds with high activities. Inhibition activity against the cancer cell lines classified according to the disease, c-Met, and PAINS of the synthesized compounds were measured. CONCLUSION: Compounds 3, 13a, 13b, 14a, 16f, 17a, 28, 30a, and 31were the most cytotoxic compounds toward the six cancer cell lines. Inhibition toward cancer cell lines classified according to the disease showed that, in most cases, the presence of the electronegative CN and or Cl groups within the molecule was responsible for its high activity.

Validity and reliability of smartphones in measuring joint position sense among asymptomatic individuals and patients with knee osteoarthritis: A cross-sectional study.

BACKGROUND: Quantifying proprioception deficit in patients with osteoarthritis (OA) may be important in evaluating treatment effectiveness. This study investigated the concurrent and known-groups validity as well as test-retest reliability of a smartphone application in assessing joint position sense (JPS) in asymptomatic individuals and patients with knee OA. METHODS: Sixty-four knees, from 16 asymptomatic controls and 16 patients with bilateral OA, were assessed twice with a 1-week interval in between. The smartphone Goniometer Pro application and isokinetic dynamometer simultaneously quantified JPS, in terms of absolute repositioning error (RE) angle, during active and passive limb movements at selected angles. RESULTS: Both devices showed moderate to almost perfect correlations in measuring JPS; whether active (intra-class correlation coefficient (ICC) >0.87) or passive (ICC >0.97). The mean RE angle differences between the two devices were <0.77° (passive JPS) and <2.76° (active JPS). Both devices were capable of distinguishing patients and asymptomatic controls at 55° and 80°. The smartphone showed moderate test-retest reliability of active JPS measurement (ICC = 0.51) in the two groups, similar to that of the isokinetic dynamometer (ICC = 0.62), but with a high measurement error. CONCLUSIONS: Smartphone application is a valid alternative to the isokinetic dynamometer in assessing JPS in patients with knee OA and asymptomatic controls. The two devices could distinguish patients and asymptomatic volunteers during passive JPS measured at 55° and 80°. Both devices have moderate reliability in quantifying active JPS, but reliability results should be considered with caution.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

PURPOSE: To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. METHODS: One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. CONCLUSIONS: Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

Validity and reliability of smartphone use in assessing balance in patients with chronic ankle instability and healthy volunteers: A cross-sectional study.

BACKGROUND: Chronic ankle instability (CAI) is associated with defective posture control and balance; thus, a proper assessment of these impairments is necessary for effective clinical decision-making. There is a need for portable, valid, and reliable methods to facilitate the easy collection of real-world data, such as mobile phones. RESEARCH QUESTION: Is the smartphone "MyAnkle" application valid and reliable in assessing balance in patients with CAI and healthy volunteers? METHODS: This was a cross-sectional study. Sixty-five participants completed two assessment sessions, including 31 patients (n = 41 ankles with CAI and 21 asymptomatic ankles) and 34 healthy volunteers (n = 68 ankles). In each session, dynamic single-leg stance balance was measured simultaneously using the "MyAnkle" application and the Biodex balance system (BBS) version 3. Testing was conducted at three levels of BBS difficulty-4 (D4, hard, loose platform), 6 (D6, moderate), and 8 (D8, easy, stiffer platform)-and repeated with opened and closed eyes. Both limbs were tested in a random order by two independent blinded assessors. RESULTS: The two devices showed significant poor-to-moderate correlations when eyes were closed (p < 0.05). For discriminant validity, the application did not distinguish the two study groups in all tested conditions (p > 0.05), whereas the BBS weakly to moderately distinguished the dominant limbs in the two groups at all difficulty levels with eyes-open and at D8 with eyes-closed regardless to limb dominance. For reliability, a significantly poor to moderate inter-session reliability was noted for the two devices. SIGNIFICANCE: "MyAnkle" application is valid in assessing balance in patients with CAI when the eyes are closed. However, similarly to BBS, its one-week test-retest reliability may be insufficient for accurate follow-up of balance changes and need to be interpreted with caution. Future studies need to establish its inter-tester reliability and its usefulness in telerehabilitation.

Relationship between binge eating and associated eating behaviors with subcortical brain volumes and cortical thickness.

BACKGROUND: Binge eating disorder (BED) is the most prevalent eating disorder. We examined the presence of binge eating (BE) and three associated eating behaviors in relation to subcortical regional volumes and cortical thickness from brain scans. METHODS: We processed structural MRI brain scans for 466 individuals from the Nathan Kline Institute Rockland Sample using Freesurfer. We investigated subcortical volumes and cortical thicknesses among those with and without BE and in relation to the scores on dietary restraint, disinhibition, and hunger from the Three-Factor Eating Questionnaire (TFEQ). We conducted a whole-brain analysis and a region of analysis (ROI) using a priori regions associated with BE and with the three eating factors. We also compared scores on the three TFEQ factors for the BE and non-BE. RESULTS: The BE group had higher scores for dietary restraint (p = .013), disinhibition (p = 1.22E-07), and hunger (p = 5.88E-07). In the whole-brain analysis, no regions survived correction for multiple comparisons (FDR corrected p<0.01) for either BE group or interaction with TFEQ. However, disinhibition scores correlated positively with left nucleus accumbens (NAc) volume (p < 0.01 FDR corrected). In the ROI analysis, those with BE also had greater left NAc volume (p = 0.008, uncorrected) compared to non-BE. LIMITATIONS: Limitations include potential self-report bias on the EDE-Q and TFEQ. CONCLUSIONS: The findings show that BE and disinhibition scores were each associated with greater volumes in the left NAc, a reward area, consistent with a greater drive and pleasure for food.

Uses of cyclohexane-1,3-dione for the synthesis of 1,2,4-triazine derivatives as anti-proliferative agents and tyrosine kinases inhibitors.

Tetrahydrobenzo[b]thiophene derivatives were well known to be biologically active compounds and many of them occupy a wide range as anticancer agent drugs. One of our main aim of this work was to synthesize target molecules not only possess anti-tumor activities but also kinase inhibitors. To achieve this goal, our strategy was to synthesize a series of novel 1,2,4-triazines as efficient anticancer drugs with low cytotoxicity and good bioavailability properties using cyclohexane-1,3-dione and 3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-diazonium chloride to give the 2-(2-(2,6-dioxocyclohexylidene)hydrazinyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) as the key starting material for many heterocyclization reactions. Compound 3 was reacted with phenylisothiocyanate to give the tetrahydrobenzo[e][1,2,4]triazine derivative 5 which reacted with hydrazines to give dihydrazone derivatives. In addition, it underwent multi-component reactions with aromatic aldehydes and either malononitrile or ethyl cyanoacetate in the presence of triethylamine or ammonium acetate to produce fused pyran and fused pyridine derivatives, respectively. Compounds obtained in this work were evaluated for their c-Met kinase inhibitory potency as well as in-vitro cytotoxic activity against the six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). Molecular modeling studies were carried out for the most active compounds 5, 7a, 7b, 10c, 10e, 11c and 11f using Molecular Operating Environment (MOE) software. It was found that all the tested compounds displayed potent c-Met enzymatic activity with IC50 values ranging from 0.24 to 9.36 nM. Ten of them (5, 7a, 7b, 10c, 10e, 10f, 11b, 11c, 11d and 11f) exhibited higher potency with IC50 values less than 1.00 nM compared with foretinib (IC50 = 1.16 nM). Also those compounds possessed moderate to strong cytotoxicity against the six tested cancer cell lines in the single-digit µM range. The synthesized compounds 5, 7a, 7b, 10c, 10e, 11c and 11f were fit on the active site of c-Met kinase, with almost the same binding pattern as foretinib and higher binding energy scores (from -16.38 to -18.21 kcal/mol) compared to foretinib (-16.37 kcal/mol). A series of novel 1,2,4-triazines were synthesized and displayed potent bioactivities, indicating that these compounds could be considered as a new lead for more investigation in the future.

Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities.

BACKGROUND: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery. OBJECTIVE: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors. METHODS: The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents. RESULTS: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50's 0.29, 0.68, and 0.42µM, respectively, against the A549 cell line. CONCLUSION: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.

New Approaches for the Uses of Cyclohexan-1,4-dione for the Synthesis of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-b]pyridine Derivatives used as Potential Anti-prostate Cancer Agents and Pim-1 Kinase Inhibitors.

BACKGROUND: Among the wide range of heterocycles, tetrahydrobenzothienopyridine derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the thiophene nucleus were known in the market. METHOD: A series of tetrahydrobenzothienopyridine derivatives were synthesized from the reaction of 2-amino- 3-benzoyl-4,5-dihydrobenzo[b]thiophen-6(7H)-one, synthesized and used for further heterocyclization reactions through reaction with different reagents. RESULTS: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. CONCLUSION: The inhibition of the newly synthesized compounds towards c-Met kinase, the five c-Metdependent cancer cell lines (A549, HT-29, MKN-45, U87MG, and SMMC-7721) and one c-Met-independent cancer cell line (H460) were investigated using foretinib as a standard drug. The results showed that compounds 6b, 7e, 9b, 9e, 16c and 20d were more active than foretinib. Furthermore, compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity, where compounds 16b and 16c were of high potencies with IC50 values of 0.28 and 0.32 µM, while compounds 6b and 13b were less effective (IC50 > 10 µM).

Synthesis, Cytotoxic and Anti-proliferative Activity of Novel Thiophene, Thieno[2,3-b]pyridine and Pyran Derivatives Derived from 4,5,6,7-tetrahydrobenzo[b]thiophene Derivative.

Novel tetrahydrobenzo[b]thienopyrole derivatives are synthesized from 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (1) through its reaction with α-chloroacetone to give the corresponding N-alkyl derivative 3. Compound 3 undergoes ready cyclization in sodium ethoxide solution to give the tetrahydrobenzo[b]thienopyrrole 4. The latter compound 4 is used as the key starting material for the synthesis of thiophene, thieno[2,3-b]pyridine and pyran derivatives. The cytotoxicity of the synthesized products towards the human cancer cell lines namely gastric cancer (NUGC), colon cancer (DLD-1), liver cancer (HA22T and HEPG-2), breast cancer (MCF-7), nasopharyngeal carcinoma (HONE-1) and normal fibroblast (WI-38) cell lines are measured. Compounds 4, 7a, 7b, 8a, 8b, 10c, 10d, 10f, 12a, 12b, 14b and 15b exhibit the optimal cytotoxic effect against cancer cell lines. Compounds 7b and 14b show the maximum inhibitory effect and these are much higher than the reference CHS-828 (pyridyl cyanoguanidine). On the other hand, the anti-proliferative evaluations of these compounds with high potency against the cancer cell lines L1210, Molt4/C8, CEM, K562, K562/4 and HCT116 show that compounds 7b and 8b give IC50's against Molt4/C8 and CEM cell lines higher than that of the reference, doxorubicin.

Cytotoxicity and Anti-proliferative Properties of Heterocyclic Compounds Derived from Progesterone.

The following study explored the cytotoxic effect on human cancer cells of a series of novel progesterone derivatives through the synthesis of heterocyclic compounds incorporating progesterone moiety. The reaction of progesterone (1) with cyanoacetanilide derivatives gave the condensation products 3a,b. Either of compound 3a or 3b reacted with elemental sulfur affording the thiophene derivatives 4a and 4b, respectively. In addition, progesterone (1) underwent some multi-component reactions with aromatic aldehydes and cyanomethylene reagents in triethylamine to give the pyran derivatives 10a-f. Carrying the same reactions but using ammonium acetate afforded the pyridine derivatives 11a-f. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that nine compounds (3b, 7c, 10b, 10d, 10f, 11d, 13a, 13b and 14b) revealed optimal cytotoxic effect against cancer cell lines with IC50 ˂ 550 nM and their cytotoxicity's were higher than that of progesterone. Moreover, the toxicity of the most active compounds was measured against shrimp larvae. In addition, the anti-proliferative evaluations of these potent compounds were measured.

Synthesis and Cytotoxic Evaluation of Pyran, Dihydropyridine and Thiophene Derivatives of 3-Acetylcoumarin.

A series of coumarin analogues bearing 4H-pyran rings 2a-d, 11a-d and 1,4-dihydropyridine rings 3a-d, 12a-d at position 3 were synthesized starting from either 3-acetyl coumarin (1) or the coumarin acetohydrazide derivative 4. Condensation of 3-acetylcoumarin (1) with 2-cyanoacetohydrazide afforded 2-cyano-N'-{1-[2-oxo-2H-chromen-3-yl]ethylidene}acetohydrazide (4). Reaction of compound 4 with elemental sulfur and either malononitrile or ethyl cyanoacetate afforded the thiophene derivatives 8 and 9, respectively. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All synthesized compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Several compounds showed potent inhibition with an IC50 value of ˂870 nM. Compound 3d exhibited equivalent cytotoxic effect as the standard CHS 828 against a breast cancer cell line (IC50 value=18 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 value >10000 nM).

Synthesis, Characterization, Antimicrobial Screening and Free-Radical Scavenging Activity of Some Novel Substituted Pyrazoles.

The present work deals with the synthesis of acetoxysulfonamide pyrazole derivatives, substituted 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives starting from substituted vanillin chalcones. Acetoxysulfonamide pyrazole derivatives were prepared from the reaction of chalcones with p-sulfamylphenylhydrazine followed by treatment with acetic anhydride. At the same time 4,5-dihydropyrazole-1-carbothioamide and 4,5-dihydropyrazole-1-isonicotinoyl derivatives were prepared from the reaction of chalcones with either thiosemicarbazide or isonicotinic acid hydrazide, respectively. The synthesized compounds were structurally characterized on the basis of IR, 1H-NMR, 13C-NMR spectral data and microanalyses. All of the newly isolated compounds were tested for their antimicrobial activities. The antimicrobial screening using the agar well-diffusion method revealed that the chloro derivatives are the most active ones. Moreover, the antioxidant and anti-inflammatory activity of these chloro derivatives are also studied using the DPPH radical scavenging and NO radical scavenging methods, respectively.

Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Mannich bases.

A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a-d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a-d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a-d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a-d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a-d with formaldehyde and various secondary amines furnished the Mannich bases 6a-p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).

Synthesis and antitumor evaluation of novel dihydropyrimidine, thiazolo[3,2-a]pyrimidine and pyrano[2,3-d]pyrimidine derivatives.

A simple and efficient method has been developed for the synthesis of 4,5-dihydro-2-mercapto-4-oxo-6-substituted arylpyrimidine derivatives (2a-e) and their fused rings (3b, 4b, 5b & 6b) and also 1,4-dihydro-2-mercaptopyrimidine derivatives (7a-e) & (9a-e) using triethylamine as a catalyst. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analysis. All the synthesized compounds were evaluated for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Thirteen of the tested compounds: 2a-e, 3b, 4b, 5b, 7d, 8, 9a, 9c and 9d exhibited significant cytotoxicity against most cell lines. Among these derivatives compounds 2a, 3b and 9c are the most potent, they exhibited cytotoxic effect against the six cancer cell lines with IC(50) values < 330 nM compared to the standard CHS 828. Normal fibroblast cells (WI38) were affected to a much lesser extent (IC(50) >10,000 nM).

Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents.

A series of new N-substituted-3-mercapto-1,2,4-triazoles (3a,b and 7a-d), triazolo[1,3,4]thiadiazines (5a,b) and triazolo[1,3,4]thiadiazoles (4a-d, 6 and 8a-d) have been synthesized starting from isonicotinic acid hydrazide. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against 6 human cancer cell lines and normal fibroblasts. Seven of the tested compounds (3a,b, 4c, 5a and 8b-d) exhibited significant cytotoxicity against most cell lines. Among these derivatives compound 4c exhibited equivalent cytotoxic effect to the standard CHS 828 against gastric cancer cell line (IC50 = 25 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM).