Tamer M. Abdelghany

Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall

The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O2-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O2-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.

Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 μM ranging from 0.495 to 5.57 μM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 μM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer.

Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties.

A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis.

Vitamin E mitigates cisplatin-induced nephrotoxicity due to reversal of oxidative/nitrosative stress, suppression of inflammation and reduction of total renal platinum accumulation

Cisplatin (CP) is one of the most effective chemotherapeutic agents. Unfortunately, CP‐induced nephrotoxicity hampered its use. This study aims to investigate the effect of vitamin E (Vit E) on CP‐induced nephrotoxicity. Male white albino rats were divided to four groups six rats each and received either, 1% tween 80 in normal saline or Vit E (75 mg/kg) per day for 14 consecutive days or a single injection of CP (6 mg/kg) alone or CP (6 mg/kg) together with Vit E (75 mg/kg per day for 14 consecutive days). Five days after the CP injection, rats were euthanized; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly increased serum levels of creatinine and urea. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CP treatment. Vit E successfully lowered serum levels of urea and creatinine, enhanced creatinine clearance and diuresis, and normalized relative kidney/body weight. Furthermore, Vit E successfully normalized renal MDA and nitrite concentrations, elevated GSH level, and restored CAT and SOD activities in renal tissues. Histopathological examination of rat kidney revealed that Vit E significantly mitigated CP‐induced renal damage. Importantly, administration of Vit E reduced kidney total platinum concentration indicating a role of platinum renal accumulation on the ability of Vit E to protect against CP nephrotoxicity.

Antiproliferative effects of triterpenoidal derivatives, obtained from the marine sponge Siphonochalina sp., on human hepatic and colorectal cancer cells.

Abstract Three triterpenoidal derivatives [Sipholenol A (1), sipholenol L (2) and sipholenone A (3)] were isolated from the Red Sea sponge Siphonochalina sp. The structures were determined based on spectroscopic measurements (NMR, UV, IR and MS). The isolated compounds were evaluated for their cytotoxic activity against three cancer cell lines; HepG2, Caco-2 and HT-29. Moreover, the effects of these metabolites on cell cycle progression as well as cell cycle regulating proteins were assessed. Compounds 1, 2 and 3 showed moderate activity against HepG2 cells with IC50 values of 17.18 ± 1.18, 24.01 ± 0.59 and 35.06 ± 1.10 μM, respectively. Compounds 1 and 2 exerted a considerable antiproliferative effect with IC50 values of 4.80 ± 0.18 and 26.64 ± 0.30 μM, respectively, against Caco-2 cells. Finally, 1 and 2 exhibited antiproliferative activity against colorectal cancer cells (HT-29) with IC50 values of 24.65 ± 0.80 and 4.48 ± 0.1 μM, respectively. Cell cycle analysis indicated that these compounds induced cell cycle arrest particularly in G0/G1 and S phases. Furthermore, the triterpenoids increased the expression of cyclin-B1, cyclin-D1 and cleaved caspase-3, as determined by immunofluorescence, indicating an important role of apoptosis in cell death induced by these compounds.

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors.

Abstract Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50 of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50 values.

All-trans retinoic acid potentiates cisplatin-induced kidney injury in rats: impact of retinoic acid signaling pathway

Cisplatin (cis-diammine dichloroplatinum (II), CDDP) is a widely used drug for treatment of various types of cancers. However, CDDP-induced nephrotoxicity remains the main dose-limiting side effect. Retinoids are a group of vitamin A-related compounds that exert their effects through retinoid receptors activation. In this study, we investigated the effect of CDDP treatment on retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α) expression. In addition, we investigated the possible modulatory effects of RAR agonist, all-trans retinoic acid (ATRA), on CDDP-induced nephrotoxicity. Rats were treated with saline, DMSO, CDDP, ATRA, or CDDP/ATRA. Twenty-four hours after the last ATRA injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CDDP treatment significantly increased serum levels of creatinine and urea, with concomitant decrease in serum albumin. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CDDP treatment. Furthermore, CDDP markedly upregulated tubular RAR-α, RXR-α, fibrin, and inducible nitric oxide synthase (iNOS) protein expression. Although administration of ATRA to control rats did not produce marked alterations in kidney function parameters, administration of ATRA to CDDP-treated rats significantly exacerbated CDDP-induced nephrotoxicity. In addition, CDDP/ATRA co-treatment significantly increased RAR-α, RXR-α, fibrin, and iNOS protein expression compared to CDDP alone. In conclusion, we report, for the first time, the crucial role of retinoid receptors in CDDP-induced nephrotoxicity. Moreover, our findings indicate that co-administration of ATRA with CDDP, although beneficial on the therapeutic effects, their deleterious effects on the kidney may limit their clinical use.

Synthesis, Anticancer Activity, Effect on Cell Cycle Profile, and Apoptosis-Inducing Ability of Novel Hexahydrocyclooctathieno[2,3-d]pyrimidine Derivatives

A novel series of hexahydrocyclooctathieno[2,3-d]pyrimidines was synthesized. Investigation of the anticancer activity of these derivatives revealed that compounds 2a and b showed broad-spectrum anticancer activity in nanomolar to micromolar concentrations. In particular, compound 2b showed a concentration required for 50% inhibition of cell growth (GI50) value of less than 1 µM against 20 cancer cell lines. Compounds 2a and b induced G2/M- and S-phase cell cycle arrest in human colon adenocarcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines with a concomitant increase in the pre-G cell population in a time-dependent manner. Furthermore, compound 2b increased the nuclear expression of the proapoptotic protein cleaved caspase-3, indicating that apoptosis has an important role, at least in part, in the cancer cell death induced by the new compounds.

Synthesis, antitumor screening and cell cycle analysis of novel benzothieno[3,2-b]pyran derivatives

Abstract Three series of benzothiophene derivatives were designed and synthesized as cytotoxic agents. The compounds were subjected to in vitro antitumor screening at the National Cancer Institute (NCI), Bethesda, MD. The results of the single dose screening indicated that only the benzothieno[3,2-b]pyran series 3a–f exhibited potent and broad spectrum cytotoxic activity and was subjected to five dose cytotoxic screening. The most active compound in this study was 2-amino-6-bromo-4-(4-nitrophenyl)-4H-[1]benzothieno[3,2-b]pyran-3-carbonitrile (3e) with MG-MID GI50, TGI, and LC50 values of 0.11, 7.94 and 42.66 μM, respectively. Compound 3e exhibited broad spectrum anticancer activity against a panel of 59 cell lines. To elucidate the underlying mechanism of compound 3e cytotoxic activity, we examined its effect on cell cycle progression and its ability to induce apoptosis using human colon adenocarcinoma cell line (HCT-116). The effect of compound 3e on the cell cycle progression indicated that exposure of HCT-116 cells to compound 3e for 24 and 48 h, induced a significant disruption in the cell cycle profile including time dependent decrease in cell population at G1 phase with concomitant increase in pre-G and G2/M cell population. Moreover, compound 3e induced time dependent increase in the percentage of early and late apoptotic and necrotic cell population. In conclusion, we were able to successfully design a new series of benzothieno[3,2-b]pyran derivatives with potent cytotoxic activity and their mechanism of cytotoxicity was examined.

Crocin Abrogates Carbon Tetrachloride-Induced Renal Toxicity in Rats via Modulation of Metabolizing Enzymes and Diminution of Oxidative Stress, Apoptosis, and Inflammatory Cytokines

This work aimed at investigating the potential modulatory effects and mechanisms of crocin against CCl4‐induced nephrotoxicity. Forty male rats were allocated for three weeks treatment with corn oil, CCl4, crocin, or crocin plus CCl4. Crocin effectively mitigated CCl4‐induced kidney injury as evidenced by amelioration of alterations in kidney histopathology, renal weight/100 g body weight ratio and kidney functions. Crocin modulated CCl4‐induced disturbance of kidney cytochrom‐P450 subfamily 2E1 and glutathione‐S‐transferase. The attenuation of crocin to kidney injury was also associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of renal glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. Crocin mitigated CCl4‐induced elevation of the renal levels of tumor necrosis factor‐alpha, interleukin‐6, prostaglandin E2, and active caspases‐3. Collectively, crocin alleviated CCl4‐induced renal damage via modulation of kidney metabolizing enzymes, suppression of oxidative stress, inhibition of inflammatory cytokines, PGE2, and active caspase3 in kidney.