Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 µM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.

Thiazolopyrimidine Scaffold as a Promising Nucleus for Developing Anticancer Drugs: A Review Conducted in Last Decade.

The thiazolopyrimidine nucleus is a bioisosteric analog of purine and an important class of N-containing heterocycles. Thiazolopyrimidine scaffolds are considered a promising class of bioactive compounds that encompass diverse biological activities, such as antibacterial, antiviral, antifungal, anticancer, corticotrophin-releasing factor antagonists, anti-inflammatory, antituberculosis, and glutamic receptors antagonists. Despite the importance of thiazolopyrimidines from a pharmacological viewpoint, there is hardly a comprehensive review on this important heterocyclic nucleus. Throughout the years, those scaffolds have been studied extensively for its anticancer properties and several compounds were designed, synthesized, and evaluated for their anticancer effects with activity in the µM to nM range. However, there are hardly any reviews covering the anticancer effects of thiazolopyrimidines. In this review, an effort was made to compile literature covering the anticancer activity of thiazolopyrimidines reported in the last decade (2010-2020). Nearly thirty articles were reviewed and compounds with IC50 < 50 µM against at least 50% of the used cell lines were listed in this review. The best ten compounds (10a, 14b, 17g, 18, 25e, 25k, 34e, 41i, 49a and 49c) showing the best anticancer activity against the corresponding cell lines during the last 10 years are highlighted. By highlighting the most active compounds, this review article sheds light on the structural features associated with the strongest anticancer effects to provide guidance for future research aiming to develop anticancer molecules.

Structural optimization, synthesis and in vitro synergistic anticancer activities of combinations of new N3-substituted dihydropyrimidine calcium channel blockers with cisplatin and etoposide.

T-type calcium channels are considered potential drug targets to combat cancer. Combining T-type calcium channel blockers with conventional chemotherapy drugs represents a promising strategy towards successful cancer treatment. From this perspective, we report in this study the design and synthesis of a novel series of N3-sustituted dihydropyrimidines (DHPMs) as anticancer adjuvants to cisplatin (Cis) and etoposide (Eto). Full spectral characterization of the new compounds was done using FT-IR, 1H NMR, 13C NMR, and HRMS. Structure elucidation was confirmed by 2D NMR 1H-H COSY, HSQC and NOESY experiments. Novel derivatives were tested for their Ca2+ channel blocking activity by employing the whole cell patch-clamp technique. Results demonstrated that most compounds were potential T-type calcium channel blockers with the triazole-based C12 and C13 being the most selective agents against CaV3.2 channel. Further electrophysiological studies demonstrated that C12 and C13 inhibited CaV3.2 currents with respective affinity of 2.26 and 1.27 µM, and induced 5 mV hyperpolarizing shifts in the half-inactivation potential. Subsequently, C12 and C13 were evaluated for their anticancer activities alone and in combination with Cis and Eto against A549 and MDA-MB 231 cancer cells. Interestingly, both compounds exhibited potential anticancer effects with IC50 values < 5 µM. Combination studies revealed that both compounds had synergistic effects (combination index CI < 1) on Cis and Eto through induction of apoptosis (p53 activation and up-regulation of BAX and p21 gene expression). Importantly, in silico physicochemical and ADMET assessment of both compounds revealed their potential drug-like properties with decreased risk of cardiac toxicity. Hence, C12 and C13 are promising anticancer adjuvants through inhibition of CaV3.2 T-type calcium channels, thereby serving as eminent leads for further modification.

Modified oblique high tibial osteotomy with minimal fixation for correction of adolescent tibia vara: a prospective case series study.

PURPOSE: To assess the reliability and efficacy of the modified oblique high tibial osteotomy for correction of complex deformity in adolescent tibia vara. METHODS: A total of 19 patients (25 legs) with adolescent tibia vara were enrolled in this study. There were 16 male (84.2%) and three female (15.8%) patients who had modified Rab oblique osteotomy with minimal fixation performed. The age of the patients at time of surgery ranged from 12 years to 30 years (mean 17.23 (sd 5.27)). The body mass index ranged from 22 kg/m2 to 42 kg/m2 (mean 32.05 (sd 6.13)). All patients were followed up for over two years (mean 3.4; 2 to 5). RESULTS: The femoro-tibial angle was improved from -34° to -12° (mean -20.04° (sd 5.24°) preoperatively and from -12° to 7°, postoperatively (mean 2.04° (sd 4.07)). Medial deviation of the mechanical axis corrected from 38 mm to 125 mm (mean 76.13 (sd 23.29)) preoperatively to 0 mm to 36 mm (mean 5.74 (sd 7.3)) postoperatively. The time needed to achieve union ranged from eight weeks to 16 weeks (mean 10.2 (sd 2.42)). According to the Lysholm functional knee score scale, there were 15 excellent (78.9%), two good (10.5%), one fair (5.2%) and one poor (5.2%) after correction of the deformity. CONCLUSION: Modified Rab osteotomy with minimal fixation by two or three screws shows promising results with good correction of varus deformity (coronal plane), internal torsion (axial plane) and procurvatum (sagittal plane), in management of adolescent tibia vara with minimal morbidity and complications. LEVEL OF EVIDENCE: IV.

Arthrodiastasis in the management of Perthes disease: a systematic review.

This systematic review explores the relevant literature to assess the efficacy of the use of arthrodiastasis in the management of Perthes disease. Until this moment, arthrodiastasis is not well established for its use in Perthes disease as opposed to other containment procedures. Furthermore, there are no clear indications for its use in this disease. Twelve articles were matched to the inclusion criteria and all articles were reviewed and radiological and clinical data were collected and compiled. As regards the hip flexion range of motion, the average preoperative flexion range of motion was 55.32°, while the postoperative was 90°. The average preoperative hip abduction range of motion was 12.28° and postoperative was 35.28°. Mean preoperative hip internal rotation range of motion was 8.69° and postoperatively was 24.93°. Mean preoperative external rotation range of motion was 21.73°, while the postoperative range was 33.71°. Final Stulberg classification was ascertained showing most patients ending with stages two and three. Complications were also assessed with most of which being superficial pin tract infections. The use of arthrodiastasis is a valid treatment option for Perthes disease; however, more articles need to be produced showing comparative data of arthrodiastasis versus other containment procedures. Level of evidence - level 1: systematic review.

Synthesis of some new C2 substituted dihydropyrimidines and their electrophysiological evaluation as L-/T-type calcium channel blockers.

Drugs targeting different calcium channel subtypes have strong therapeutic potential for future drug development for cardiovascular disorders, neuropsychiatric diseases and cancer. This study aims to design and synthesize a new series of C2 substituted dihydropyrimidines to mimic the structure features of third generation long acting dihydropyridine calcium channel blockers and dihydropyrimidines analogues. The target compounds have been evaluated as blockers for CaV1.2 and CaV3.2 utilizing the whole-cell patch clamp technique. Among the tested compounds, compound 7a showed moderate calcium channel blockade activity against CaV3.2. Moreover, the predicted physicochemical properties and pharmacokinetic profiles of the target compounds recommend that they can be considered as drug-like candidates. The results highlight some significant information for the future design of lead compounds as calcium channel blockers.

Selective antagonism of CRF1 receptor by a substituted pyrimidine.

The corticotrophin-releasing factor (CRF) and its type 1 receptor (CRF1R) regulate the hypothalamic-pituitary-adrenal axis, as well as other systems, thus playing a crucial role in the maintenance of homeostasis. Non-peptide CRF1R-selective antagonists exert therapeutic effects on experimental animals with abnormal regulation of their homeostatic mechanisms. However, none of them is as yet in clinical use. In an effort to develop novel small non-peptide CRF1R-selective antagonists, we have synthesized a series of substituted pyrimidines described in a previous study. These small molecules bind to CRF1R, with analog 3 having the highest affinity. Characteristic structural features of analog 3 are a N,N-bis(methoxyethyl)amino group at position 6 and a methyl in the alkythiol group at position 5. Based on the binding profile of analog 3, we selected it in the present study for further pharmacological characterization. The results of this study suggest that analog 3 is a potent CRF1R-selective antagonist, blocking the ability of sauvagine, a CRF-related peptide, to stimulate cAMP accumulation in HEK 293 cells via activation of CRF1R, but not via CRF2R. Moreover, analog 3 blocked sauvagine to stimulate the proliferation of macrophages, further supporting its antagonistic properties. We have also constructed molecular models of CRF1R to examine the interactions of this receptor with analog 3 and antalarmin, a prototype CRF1R-selective non-peptide antagonist, which lacks the characteristic structural features of analog 3. Our data facilitate the design of novel non-peptide CRF1R antagonists for clinical use.

Scarf versus long chevron osteotomies for the treatment of hallux valgus: A prospective randomized controlled study.

BACKGROUND: The aim of this study is to compare scarf osteotomy and long chevron osteotomy in treatment of hallux valgus deformity regarding operative time, power of correction and complications. DESIGN: A prospective randomized controlled comparative trial. METHODS: 48 cases with hallux valgus were divided randomly in 2 groups (21 treated by scarf and 22 treated by long chevron osteotomy and 5 were missed during follow up), average age 36 years, follow up time was average of 25.9 months. Patients were assessed clinically, radiologically, and functional scoring system of American College of Foot and ankle Surgeons (ACFAS)was used both pre and postoperatively. RESULTS: Operative time was 69min in scarf group compared to 63min to long chevron group, radiological correction showed no statistically significant difference between both groups while functional improvement in ACFAS score was in favour of long chevron group 69.1% compared to scarf group 57.5% CONCLUSIONS: Both osteotomies possess almost identical corrective power of the IMA (intermetatarsal angle) and similar clinical outcomes with slightly shorter operative time and subjective technical simplicity for the long chevron osteotomy.

Thiazolo[4,5-d]pyrimidines as a privileged scaffold in drug discovery.

Thiazolo[4,5-d]pyrimidines are fused heterocyclic ring-systems that can be viewed at the first glance as purine isosteres. They are the 7 thia-analogs of purines via the replacement of the nitrogen at position 7 of the purine ring by a sulfur atom. Because of the structural resemblance to adenine and guanine and their related derivatives as adenosine, guanosine, cAMP, cGMP and similar biomolecules, many thiazolo[4,5-d]pyrimidines scaffold were developed and utilized by medicinal chemists to design novel therapeutics. Many were found to have a broad range of pharmacological activities. The outstanding development of thiazolo[4,5-d]pyrimidines within a short time span shows its magnitude of usefulness for medicinal chemistry research. Despite their importance from pharmacological and synthetic point of views, hardly there is a comprehensive review of thiazolo[4,5-d]pyrimidines applications in medicinal research to date. Thus, this review article describes the structures and medicinal significance of all classes of thiazolo[4,5-d]pyrimidines reported in literature to date. It describe the development of thiazolo[4,5-d]pyrimidines as immune-modulators, Corticotropin Releasing Factor (CRF) receptor antagonists, anti-Parkinson's, antiviral, anticancer, antibacterial, antifungal, analgesic, anti-inflammatory agents including COX inhibitors, chemokines antagonists and Fractlkine receptor antagonists.

Evaluation of anti-melanoma activities of (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol from the Red Sea soft coral Sarcophyton glaucum.

Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were evaluated for their inhibitory effects on mouse melanoma B16F10 cell growth. Results show that all the cembranoids strongly inhibit viability of melanoma cells particularly during 48 -72 hrs treatment and also inhibit de novo DNA synthesis and PARP activity and stimulate fragmentation of DNA. (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol was not cytotoxic to monkey kidney CV-1 cells at the concentration that produces the anti-melanoma effects which indicates that this compound may be a good candidate for further development. (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were found to be cytotoxic to healthy cells.

Evaluation of the anti-melanoma activities of sarcophine, (+)-7alpha,8beta-dihydroxydeepoxysarcophine and sarcophytolide from the Red Sea soft coral Sarcophyton glaucum.

Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely sarcophine (1), (+)-7alpha,8beta-dihydroxydeepoxysarcophine (2) and sarcophytolide (3) were evaluated for their potential inhibitory effects on growth of mouse melanoma B16F10 cells. Compounds (1) and (2) maximally inhibit viability of melanoma cells during 48 hr and 72 hr treatment at concentrations that show no cytotoxicity on monkey kidney CV-1 cells and also inhibit de novo DNA synthesis and PARP activity. Compound (3) produced cytotoxic effects at the same concentration range it produces its antitumor effects. These data suggest that (1) and (2), but not (3), have potential for further development as antitumor agents against melanoma.

Chemopreventive effect of sarcophine-diol on NOR-1-induced TPA-promoted skin carcinogenesis in female HOS:HR-1 mice.

The cancer chemopreventive potential of sarcophine-diol in a chemical carcinogen initiation-promotion experimental tumor model in mice was evaluated. Sarcophine-diol, when given orally, afforded significant protection in the mouse skin cancer model initiated by the topical administration of (+/-)-(E)-4-methyl-2-[(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). These findings, along with our initial reports, suggest that sarcophine-diol is an effective cancer chemopreventive agent, even when administered orally and at a very low dose and thus indicating possible potential human applications in the control of malignancy.

Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.

Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 µg SD applied topically and 180 mJ/cm(2) UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm(2). This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 µL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 µg, 45 µg, and 60 µg dissolved in 200 µL of acetone) 1 h before UVB radiation (30 mJ/cm(2)). The last group of animals received 60 µg SD/200 µL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

Sarcophine-diol inhibits expression of COX-2, inhibits activity of cPLA2, enhances degradation of PLA2 and PLC(γ)1 and inhibits cell membrane permeability in mouse melanoma B16F10 cells.

Sarcophine-diol (SD) is a semi-synthetic derivative of sarcophine with a significant chemopreventive effect against non-melanoma skin cancer both in vitro and in vivo. Recently, we have studied the effect of SD on melanoma development using the mouse melanoma B16F10 cell line. In this study, our findings show that SD suppresses cell multiplication and diminishes membrane permeability for ethidium bromide (EB), a model marker used to measure cell permeability for Ca²âº ions. SD also decreases protein levels of COX-2, and increases degradation of phospholipases PLA2 and PLC(γ)1 and diminishes enzymatic activity of the Ca²âº-dependent cPLA2. This lower membrane permeability for Ca²âº-ions, associated with SD, is most likely due to the diminished content of lysophosphosphatidylcholine (lysoPC) within cell membranes caused by the effect of SD on PLA2. The decrease in diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) due to inhibition of PLC(γ)1, leads to the downregulation of Ca²âº-dependent processes within the cell and also inhibits the formation of tumors. These findings support our previous data suggesting that SD may have significant potential in the treatment of melanoma.

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 µg), and then the effects of different honokiol doses (30, 45, and 60 µg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 µg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 µg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 µg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 µg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 µg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 µg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

Sarcophine-diol, a skin cancer chemopreventive agent, inhibits proliferation and stimulates apoptosis in mouse melanoma B16F10 cell line.

Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B16F10 cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B16F10 tumor cells.

Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action.

BACKGROUND: Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development. METHODS: UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle. RESULTS: Magnolol pretreated groups (30, 60 µ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells. CONCLUSIONS: Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.

Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells.

Honokiol is a plant lignan isolated from bark and seed cones of Magnolia officinalis. Recent studies from our laboratory indicated that honokiol pretreatment decreased ultraviolet B-induced skin cancer development in SKH-1 mice. The aim of the present investigation was to study the effects of honokiol on human epidermoid squamous carcinoma A431 cells and to elucidate possible mechanisms involved in preventing skin cancer. A431 cells were pretreated with different concentrations of honokiol for a specific time period and investigated for effects on apoptosis and cell cycle analysis. Treatment with honokiol significantly decreased cell viability and cell proliferation in a concentration- and time-dependent manner. Honokiol pretreatment at 50 µmol/L concentration induced G0/G1 cell cycle arrest significantly (P < 0.05) and decreased the percentage of cells in the S and G2/M phase. Honokiol down-regulated the expression of cyclin D1, cyclin D2, Cdk2, Cdk4 and Cdk6 proteins and up-regulated the expression of Cdk's inhibitor proteins p21 and p27. Pretreatment of A431 cells with honokiol leads to induction of apoptosis and DNA fragmentation. These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis.

Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents.

The synthesis of a novel series of 4-thiazolylpyrazolyl derivatives is described in the present report. All the newly synthesized compounds were examined for their anti-inflammatory activity using cotton pellet-induced granuloma and carrageenan-induced rat paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), ulcerogenic effect and acute toxicity were also determined. Furthermore, all compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, Staphylococcus aureus and Candida albicans. A docking pose for compounds 8b, 10a and 10b separately in the active site of the human COX-2 enzyme and DNA-gyrase B was also obtained. The results revealed that compounds 8b, 10a and 10b exhibited good anti-inflammatory activity with no or minimal ulcerogenic effect and good safety margin. Compounds 10a and 10b were found to be the most potent anti-inflammatory agents in the present study. Meanwhile, 10a and 10b displayed higher selective inhibitory activity towards COX-2 compared to indomethacin. Moreover, compounds 10a and 10b exhibited promising antibacterial against both E. coli and S. aureus. Docking studies for 8b, 10a and 10b with COX-2 (PDB ID: 1CX2) and DNA-gyrase B (PDB ID: 1EI1) showed good binding profile.

Alpha-santalol, a chemopreventive agent against skin cancer, causes G2/M cell cycle arrest in both p53-mutated human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells.

BACKGROUND: alpha-Santalol, an active component of sandalwood oil, has shown chemopreventive effects on skin cancer in different murine models. However, effects of alpha-santalol on cell cycle have not been studied. Thus, the objective of this study was to investigate effects of alpha-santalol on cell cycle progression in both p53 mutated human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells to elucidate the mechanism(s) of action. METHODS: MTT assay was used to determine cell viability in A431 cells and UACC-62; fluorescence-activated cell sorting (FACS) analysis of propidium iodide staining was used for determining cell cycle distribution in A431 cells and UACC-62 cells; immunoblotting was used for determining the expression of various proteins and protein complexes involved in the cell cycle progression; siRNA were used to knockdown of p21 or p53 in A431 and UACC-62 cells and immunofluorescence microscopy was used to investigate microtubules in UACC-62 cells. RESULTS: alpha-Santalol at 50-100 muM decreased cell viability from 24 h treatment and alpha-santalol at 50 muM-75 muM induced G2/M phase cell cycle arrest from 6 h treatment in both A431 and UACC-62 cells. alpha-Santalol altered expressions of cell cycle proteins such as cyclin A, cyclin B1, Cdc2, Cdc25c, p-Cdc25c and Cdk2. All of these proteins are critical for G2/M transition. alpha-Santalol treatment up-regulated the expression of p21 and suppressed expressions of mutated p53 in A431 cells; whereas, alpha-santalol treatment increased expressions of wild-type p53 in UACC-62 cells. Knockdown of p21 in A431 cells, knockdown of p21 and p53 in UACC-62 cells did not affect cell cycle arrest caused by alpha-santalol. Furthermore, alpha-santalol caused depolymerization of microtubules similar to vinblastine in UACC-62 cells. CONCLUSIONS: This study for the first time identifies effects of alpha-santalol in G2/M phase arrest and describes detailed mechanisms of G2/M phase arrest by this agent, which might be contributing to its overall cancer preventive efficacy in various mouse skin cancer models.