Development of a Modified Friedewald's Formula to Calculate Low-Density Lipoprotein in an Iranian Population.

Background: Elevated low-density lipoprotein cholesterol (LDL-C) is a significant risk factor for cardiovascular diseases. LDL-C can be directly measured using various methods, but this requires expensive equipment. Currently, clinical laboratories estimate LDL-C based on Friedewald's formula (FF). We aimed to develop a modified formula based on directly measured LDL-C (D-LDL-C) values in a large population in Southern Iran and compare the results with various other estimation formulas. Methods: The participants of this cross-sectional study were adults aged >18 years living in Southern Iran. Blood samples from 15,200 individuals were collected, and the measured lipid parameters were randomly divided into training (n=10,184) and validation (n=5,016) datasets. A new formula was developed using a linear regression model, and its accuracy was validated. Pearson's correlation and Cohen's kappa were used to determin the relationship between D-LDL-C and calculated LDL-C (C-LDL-C). Results: The developed formula for the estimation of LDL-C was 0.857 total cholesterol (TC)-0.915 high-density lipoprotein cholesterol (HDL-C)-0.115 triglycerides (TG). Based on our proposed formula, for TG<150 and TG≥150 mg/dL, there was a significant correlation between mean values of D-LDL-C and C-LDL-C (r=0.985 and r=0.974, respectively). Compared to other formulas, C-LDL-C obtained from the proposed formula had the highest correlation with D-LDL-C. The agreement between D-LDL-C and C-LDL-C for TC<200, 200-239, and ≥240 mg/dL was 80.8%, 63.2%, and 67.4%, respectively, indicating a higher level of agreement than other formulas. Conclusion: The new formula appears to be more accurate than FF when applied to the population of Southern Iran.

Spotlight on the Expanding Role of miR-647 in Human Cancers.

MicroRNAs are a large group of small, non-coding ssRNAs (miRNAs) that have an epigenetically pivotal role in gene expression and other biological processes in cells and can be regarded as capable biomarkers for the early detection and management of cancer. The aim of the present review article is to summarize the evidence for recognizing the molecular mechanism, target genes, and clinical significance of miR-647 in different cancers. Multiple studies have demonstrated that aberrant expression of miR-647 could be found in a variety of malignancies, such as bladder cancer, cervical cancer, colorectal cancer, gastric cancer, glioma, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, and prostate cancer have reported, notably, increase or decrease in expression of miR-647 so that it can function as a tumorigenic (oncomiR) or tumor suppressor gene. MiR-647 is effective in the proliferation, migration, and invasion of cancer cells by playing a function in cell cycle pathways. MiR-647 can be a valuable potential biomarker for assessing the extent of cancer, prognosis, and response to therapy and shows great therapeutic efficacy in different solid tumors. Moreover, serum concentrations of miR-647 are directly effective in decreasing overall survival and disease progression. So, an efficient therapeutic target can be the effect on miR-647 expression by antitumor drugs.

A Comprehensive Study on Signal Transduction and Therapeutic Role of miR-877 in Human Cancers.

MicroRNAs are a group of short non-coding RNAs (miRNAs), which are epigenetically involved in gene expression and other cellular biological processes and can be considered as potential biomarkers for cancer detection and support for treatment management. This review aims to amass the evidence in order to reach the molecular mechanism and clinical significance of miR-877 in different types of cancer. Dysregulation of miR-877 level in various types of malignancies as bladder cancer, cervical cancer, cholangiocarcinoma, colorectal cancer (CRC), gastric cancer, glioblastoma, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma, laryngeal squamous cell carcinoma, melanoma, non-small cell lung cancer (NSCLC), oral squamous cell carcinoma, ovarian cancer (OC), pancreatic ductal adenocarcinoma, and renal cell carcinoma (RCC) have reported, significantly increase or decrease in its level, which can be indicated to its function as oncogene or tumor suppressor. MiR-877 is involved in cell proliferation, migration, and invasion through cell cycle pathways in cancer. MiR-877 could be potential a candidate as a valuable biomarker for prognosis in various cancers. Through this study, we proposed that miR-877 can potentially be a candidate as a prognostic marker for early detection of tumor development, progression, as well as metastasis.

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.

The Prominent Role of miR-942 in Carcinogenesis of Tumors.

As a family of short noncoding RNAs, MicroRNAs have been identified as possible biomarkers for cancer discovery and assist in therapy control due to their epigenetic involvement in gene expression and other cellular biological processes. In the present review, the evidence for reaching the clinical effect and the molecular mechanism of miR-942 in various kinds of cancer is amassed. Dysregulation of miR-942 amounts in different kinds of malignancies, as bladder cancer, esophageal squamous cell carcinoma, breast cancer, cervical cancer, gastric cancer, colorectal cancer, Kaposi's sarcoma, melanoma, Hepatocellular carcinoma, nonsmall-cell lung cancer, oral squamous cell carcinoma, osteosarcoma, ovarian cancer, pancreatic ductal adenocarcinoma, renal cell carcinoma, and prostate cancer has stated a considerable increase or decrease in its level indicating its function as oncogene or tumor suppressor. MiR-942 is included in cell proliferation, migration, and invasion through cell cycle pathways, including pathways of transforming growth factor-beta signaling pathways, Wnt pathway, JAK/STAT pathway, PI3K/AKT pathway, apoptosis pathway, hippo signaling pathway, lectin pathway, interferon-gamma signaling, signaling by G-protein coupled receptor, developmental genes, nuclear factor-kappa B pathway, Mesodermal commitment pathway, and T-cell receptor signaling in cancer. An important biomarker, MiR-942 is a potential candidate for prediction in several cancers. The present investigation introduced miR-942 as a prognostic marker for early discovery of tumor progression, metastasis, and development.

Synthesis of Fused Quinoline Derivatives With Antiproliferative Activities and Tyrosine Kinases, Pim-1 Kinase Inhibitions.

Cyclohexan-1,3-dione (1) reacted with either 2-aminoprop-1-ene-1,1,3-tricarbonitrile (2a) or diethyl 3-amino-2-cyanopent-2-enedioate (2b) to give the 5,6,7,8-tetrahydronaphthalene derivatives 3a and 3b, respectively. The latter compounds underwent further heterocyclization reactions to give the thieno[2',3':5,6]benzo[1,2-e][1,3]oxazine derivatives. On the other hand, the reaction of compound 1 with trichloroacetonitrile afforded the (2,2,2-trichloroethylidene)cyclohexane derivative 14. The latter underwent a series of reactions to produce 2,3,6,7-tetrahydroquinazoline, dihydrothieno[2,3-h]isoquinoline, octahydrobenzo[h]quinazoline and dihydrothieno[2,3-h]isoquinoline derivatives. The synthesized compounds were tested toward six cancer cell lines where most of them gave high inhibitions with c-Met enzymatic activity, with tyrosine kinases and Pim-1 inhibitions. The results obtained will encourage further work through such compounds to produce optimized anticancer agents.

Design, Synthesis, Molecular Docking, and Biological Studies of New Heterocyclic Compounds Derived from ß-Diketones as Novel EGFR and Pim-1 Inhibitors Endowed with AntitumorActivity.

BACKGROUND: Cancer is a disease illustrated by a shift in the controlled mechanisms that control both cell proliferation and differentiation. It is regarded as a prime health problem worldwide and a leading cause of human death rate exceeded only by cardiovascular diseases. Many reported works are concerned with discovering new antitumor compounds, encouraging us to synthesize new anticancer agents. OBJECTIVE: In this work, we aimed to synthesize target molecules from 1,3-dicarbonyl compounds through heterocyclization reactions. METHODS: The reaction of either 4-methylaniline (1a) or 1-naphthylamine (1b) with diethyl malonate (2) gave the anilide derivatives 3a and 3b, respectively. The latter underwent a series of heterocyclization reactions to give the pyridine, pyran, and thiazole derivatives confirmed by the required spectral data. RESULTS: The in-vitro antitumor evaluation of the newly synthesized products against three cancer cell lines, MCF-7, NCI-H460, SF-268, and WI 38, which were used as the normal cell lines, was conducted, and the data revealed that compounds 11a, 18b, 18c, and 20d showed high antitumor activity and 20d individualized with potential antitumor activity towards cell lines with lowest cytotoxicity effect. Both EGFR and PIM-1 enzymes inhibition were investigated for the compound 20d, and it was found that the inhibition effect of compound 20d was promising for each enzyme, showing IC50 = 45.67 ng and 553.3 ng for EGFR and PIM-1, respectively. CONCLUSION: Molecular docking results of compound 20d showed strong binding interactions with both the enzymes, where good binding modes were obtained in the case of EGFR, which was closely similar to the binding mode of standard Erlotinib.While 20d showed complete superimposition binding interactions with VRV-cocrystallized ligand of PIM-1 that may expound the in-vitro antitumor activity.

A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients.

In COVID-19 patients, cytokine storm due to excessive immune responses can cause severe complications. In this study, we investigated the effect of curcumin nanomicelles on clinical outcome and cellular immune responses subtypes changes in COVID-19 patients. A randomized, triple-blinded, placebo-controlled study was done. Forty COVID-19 patients were included into two groups of nano-curcumin and placebo. The nano-curcumin group received 40 mg of nano-curcumin capsule, four times per day for 2 weeks. Clinical signs and gene expression of TBX21, GATA3, RORC and FOXP3 genes and IFN-γ, IL-4, IL-17 and TGF-ß cytokines serum levels were measured at time points of 0, 7 and 14 days. Serum levels of IFN-γ (p = .52) and IL-17 (p = .11) decreased, while IL-4 (p = .12) and TGF-ß (p = .14) increased in the nano-curcumin group compared with placebo on day 14. Moreover, gene expressions of TBX21 (p = .02) and FOXP3 (p = .005) genes were significantly decreased and increased between nano-curcumin and placebo groups on day 7, respectively. It can be concluded that administration of nano-curcumin in inflammatory phase of COVID-19 can accelerate recovering of the acute inflammatory phase by modulating inflammatory immune responses. Therefore, it is suggested that this supplement in inflammatory diseases, including COVID-19, can be effective in controlling the inflammatory responses.

The Effect of HBB: c.-121C>T Variant [-71 (C>T)] on the ß-Globin Promoter: Case Series Study.

One of the effective strategies in controlling thalassemia is recognition of carriers, followed by prenatal diagnosis (PND) to prevent the occurrence of new cases. There are some rare mutations and variants, for which there are not enough evidences of their effects, and can lead to misdiagnosis and even cause confusion in decision about termination of pregnancy. That is why it is very critical to know the effect of each mutation on the ß chain gene. The variant of HBB: c.-121C>T [-71 (C>T)] located in the CAAT box of the promoter region, is a rare mutation. We report seven patients in Hormozagn Province, Iran, who were referred to the PND Center of Hormozgan University of Medical Science (HUMS), Bandar Abbas, Iran during 10 years (2010-2020). Briefly, this mutation causes minor changes in blood indices [mean corpuscular volume (MCV): 75.0 ± 4.0 fL; mean corpuscular hemoglobin (MCH): 25.8 ± 2.5 pg; Hb A2: 3.4 ± 0.5%] showed anemia with a trait milder than minor ß-thalassemia (ß-thal). Though the existence of α mutations (deletions/point mutations) along with HBB: c.-121C>T can change blood indices due to the changes in α/ß ratio. The phenotype of ß-thal intermedia (ß-TI) was observed in one case, who was a compound heterozygosity for codon 15 (G>A)/-71(C>T) (HBB: c.48G>A/HBB: c.-121C>T. The analysis of transcription level by real-time polymerase chain reaction (real-time PCR) confirmed that this allele induces a mild ß+ phenotype due to a decrease in the transcription level.

New Approaches for the Synthesis of Heterocyclic Compounds Derived from Cyclohexan-1,3-dione with Anti-proliferative Activities.

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a-d and 6a-d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a-d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.

Multi-component Reactions of Cyclohexan-1,3-diketones to Produce Fused Pyran Derivatives with Antiproliferative Activities and Tyrosine Kinases and Pim-1 Kinase Inhibitions.

In this work the multi-component reactions of either of the arylhydrazocyclohexan-1,3-dione derivatives 3a-c with either of benzaldehyde (4a), 4-chlorobenzaldehyde (4b) or 4-methoxybenzaldehyde (4c) and either malononitrile (5a) or ethyl cyanoacetate (5b) giving the 5,6,7,8-tetrahydro-4H-chromene derivatives 6a-r, respectively, are presented. The reaction of two equivalents of cyclohexan-1,3-dione with benzaldehyde gave the hexahydro-1H-xanthene-1,8(2H)-dione derivative 7. On the other hand, the multi-component reactions of compound 1 with dimedone and benzaldehyde gave 13. Both of 7 and 13 underwent heterocyclization reactions to produce fused thiophene, pyran and thiazole derivatives. Selected compounds among the synthesized compounds were tested against six cancer cell lines where most of them gave high inhibitions; especially compounds 3b, 3c, 6b, 6c, 6d, 6f, 6i, 6m, 6n, 8b, 14a, 15 and 16 being the most cytotoxic compounds. Further tests against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 6c, 6d, 6f, 6n, 14a and 15 were the most potent of the tested compounds toward the five tyrosine kinases and compounds 3c, 6c, 6d, 6n and 15 displayed the highest inhibitions toward Pim-1 kinase.

The outstanding role of miR-132-3p in carcinogenesis of solid tumors.

MicroRNAs are a group of short non-coding RNAs (miRNAs), which are epigenetically involved in gene expression and other cellular biological processes and can be considered as potential biomarkers for cancer detection and support for treatment management. This review aims to amass the evidence to reach the molecular mechanism and clinical significance of miR-132 in different types of cancer. Dysregulation of miR-132 level in various types of malignancies, including hepatocellular carcinoma, breast cancer, colorectal cancer, gastric cancer, lung cancer, prostate cancer, osteosarcoma, pancreatic cancer, and ovarian cancer have reported, significantly decrease in its level, which can be indicated to its function as a tumor suppressor. miR-132 is involved in cell proliferation, migration, and invasion through cell cycle pathways, such as PI3K, TGFß or hippo signaling pathways, or on oncogenes such as Ras, AKT, mTOR, glycolysis. miR-132 could be potentially a candidate as a valuable biomarker for prognosis in various cancers. Through this study, we proposed that miR-132 can potentially be a candidate as a prognostic marker for early detection of tumor development, progression, as well as metastasis.

The expanding role of CDR1-AS in the regulation and development of cancer and human diseases.

CircRNAs are a superabundant and highly conserved group of noncoding RNAs (ncRNAs) that are characterized by their high stability and integrity compared with linear forms of ncRNAs. Recently, their critical role in gene expression regulation has been shown; thus, it is not far-fetched to believe that their abnormal expression can be a cause of different kinds of diseases such as cancer, neurodegenerative, and autoimmune diseases. They can have a function in variety of biological processes such as microRNA (miRNA) sponging, interacting with RNA-binding proteins, or even an ability to translate to proteins. A huge challenge in finding diagnostic biomarkers is finding noninvasive biomarkers that can be detected in human fluids, especially blood samples. CircRNAs are becoming candidate biomarkers for diagnosis and prognosis of these diseases through their ability to transverse from the blood-brain barrier and their broad presence in circulating exosomes. The circRNA for miRNA-7 (ciRS-7) is newly recognized, and acknowledged to being related to human pathology and cancer progression. In this review, we first briefly summarize the latest studies about their characteristics, biogenesis, and their mechanisms of action in the regulation and development of human diseases. Finally, we provide a list of diseases that are linked to one member of this novel class of ncRNAs called ciRS-7.

Synthesis of Novel Thiophene, Thiazole and Coumarin Derivatives Based on Benzimidazole Nucleus and Their Cytotoxicity and Toxicity Evaluations.

The reactivity of compounds 2-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)acetonitrile 2 and 3-(1-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)-2H-chromen-2-one 8 towards different chemical reagents were studied and a series of novel benzimidazole derivatives were obtained (2-6a-d and 8-12a-d). Moreover, in vitro growth inhibitory effect of the newly synthesized compounds were evaluated in term of [IC50 µM] against the six cancer cell lines, human lung carcinoma (A549), lung cancer (H460), human colorectal (HT29), gasteric cancer cell (MKN-45), glioma cell line (U87MG) and cellosaurus cell line (SMMC-7721) where foretinib was used as standard reference. The results showed that compounds 2 (only for A549 cell line), 3a, 4, 6c, 6d, 8, 9a, 9e and 9f were the most active compounds towards the six cancer cell lines. On the other hand, the toxicity of these most potent compounds against shrimp larvae indicated that compounds 3a, 4, 6d, 9e and 9f were non toxic while compounds 6c and 8 were very toxic and compounds 2 and 9a were harmful against the tested organisms.

Uses of Cyclohexan-1,4-dione for the Synthesis of 2-Amino-4,5-dihydrobenzo[b]thiophen-6(7H)-one Derivatives with Anti-proliferative and Pim-1 Kinase Activities.

The reaction of cyclohexan-1,4-dione with elemental sulfur and any of the 2-cyano-N-arylacetamide derivatives 2a-c gave the 2-amino-4,5-dihydrobenzo[b]thiophen-6(7H)-one derivatives 3a-c to be used in some heterocyclization reactions. The multicomponent reactions of any of compounds 3a-c with aromatic aldehydes 6a-c and either of malononitrile or ethylcyanoacetate gave the 5,9-dihydro-4H-thieno[2,3-f]chromene derivatives 9a-r, respectively. The anti-proliferative evaluation of the newly synthesized compounds against the six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 showed that the nine compounds 3c, 5c, 9e, 9h, 9i, 9j, 9l, 9q, 11e and 13e with highest cytotoxcity. Toxicity of these compounds against shrimp larvae revealed that compounds 3c, 9j, 9q, and 13e showed no toxicity against the tested organisms. The c-Met kinase inhibition of the most potent compounds showed that compounds 9j, 9q, 10e, 12e and 13e have the highest activities. Compounds 9j, 9l, 9q and 11e showed high activity towards tyrosine kinases. Moreover, compounds 9j, 9q and 13e showed the highest inhibitor activity towards Pim-1 kinase.

Synthesis of Novel Heterocyclic Compounds Incorporate 4,5,6,7-Tetrahydrobenzo[b]thiophene Together with Their Cytotoxic Evaluations.

The 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene was the key starting compound used to synthesize new thiazole, pyrimidine, pyran, pyridine and thiazine derivatives. The cytotoxicity of the synthesized compounds was studied towards the three cancer cell lines namely MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (central nervous system (CNS) cancer) in addition to the normal cell line (WI-38) using doxorubicin as the reference drug. The study showed that compounds 5, 9a, 15b, 17c, 18 and 21b were the most potent compounds.

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.

Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4H-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities.

The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a-d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a-g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a-f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a-d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a-c and arylhydraone 11a-e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a-d had optimal cytotoxic effect against cancer cell lines with IC50<550 nM. The toxicity of the most active compounds was further measured against shrimp larvae.

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 and anti-tumor evaluation of novel hydrazide and hydrazide-hydrazone derivatives.

The reaction of cyclopentanone with cyanoacetylhydrazine gave 2-cyano-2-cyclopentylideneacetohydrazide (1). Treatment of compound 1 with elemental sulphur in the presence of triethylamine afforded 2-amino-5,6-dihydro- -4H-cyclopenta[b]thiophene-3-carbohydrazide (2), which in-turn formed the corresponding intermediate diazonium salt. The latter was coupled with either ethyl cyanoacetate or ethyl acetoacetate to form 2-cyano-2-(3-(hydrazinecarbonyl)- 5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)hydrazono) acetate (3) and ethyl 2-(2-(3-(hydrazinecarbonyl)-5,6-dihydro- 4H-cyclopenta[b]thiophen-2-yl)hydrazono)-3-oxobutanoate (4), respectively. On the other hand, the reaction of compound 1 with either benzaldehyde or acetophenone afforded N'-benzylidene-2-cyano-2-cyclopentylideneacetohydrazide (7) and 2-cyano-2-(2-cyclopentylidene)phenylacetohydrazide (10), respectively. Moreover, compound 1 was used to synthesize 2-cyano-2-cyclopentylidene- N'-(arylthiazol-2(3H)-ylidene)acetohydrazides (6a,b), 2-(2-benzylidenecyclopentylidene)-2-cyanoacetohydrazide (8), 2-amino-N'-benzylidene-5,6-dihydro-4H- -cyclopenta[b]thiophene-3-carbohydrazide (9), 2-cyano- -2-(2-(2-phenylhydrazono)cyclopentylidene)acetohydrazide (11), N'-(1-chloropropan-2-ylidene)-2-cyano-2-cyclopentylideneacetohydrazide (12), and 2-cyclopentylidene-3- -(3,5-disubstituted-1H-pyrazol-1-yl)-3-oxopropanenitriles (13a,b) through its reaction with the respective reagents. Antitumor evaluation of the newly synthesized compounds against the three human tumor cells lines, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) showed that some of the described compounds exhibited higher inhibitory effects towards the three tumor cell lines than the reference compound doxorubicin.