Design, synthesis and antitumor evaluation of novel thalidomide dithiocarbamate and dithioate analogs against Ehrlich ascites carcinoma-induced solid tumor in Swiss albino mice

A series of 16 novel thalidomide sulfur analogs containing one and two sulfur atoms 2 and 4-18, respectively, were designed and synthesized. These compounds were screened for in vitro antitumor activity against Ehrlich ascites carcinoma (EAC) cell line and exhibited potent cytotoxic activity. On the bases of the obtained results for in vitro cytotoxic activity, thalidomide sulfur analogs containing two sulfur atoms 8, 9, 13 and 14 were selected and tested in vivo against EAC-induced solid tumor in female mice compared to thalidomide 1 as well as its analog 2 and exhibited a highly significant reduction in tumor volume (TV). Results illustrated the antioxidative activity of these compounds as the level of hepatic lipid peroxidation decreased and levels of antioxidant enzymes like superoxide dismutase (SOD) and catalase were elevated. The histopathological investigations revealed that thalidomide sulfur analogs 2, 8, 9, 13 and 14 have antimitotic, apoptotic and necrotic activities against solid tumor. These compounds lead to increase of Fas-L expression. The immunohistochemical studies showed a decrease in Ki67 and vascular endothelial growth factor (VEGF) staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate and angiogenic process associated with tumor growth. Compounds 9 and 13 were the most potent compounds in tumor necrosis without liver necrosis. At the same time, treatment with compound 9 resulted in liver degeneration.     

C-2-aryl O-substituted HI-236 derivatives as non-nucleoside HIV-1 reverse-transcriptase inhibitors

Several novel thiourea derivatives of the NNRTI HI-236 substituted at the C-2 oxygen of the phenyl ring have been synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-2 cell cultures. The compounds were synthesized in order to fine-tune the activity of HI-236 as well as to gain insight into spatial characteristics in the pocket pertaining to the positional choice of tether in the design of [NRTI]-tether-[HI-236] bifunctional inhibitors. Two of the thiourea derivatives bearing a butynyl (6c) or hydroxyethyl tether (6n) were endowed with improved anti-HIV activity compared to HI-236. NNRTI activity was confirmed by a cell-free RT assay on six of the derivatives in which 6c returned an IC(50) of 3.8 nM compared to 28 nM for HI-236, establishing it as an improved lead for HI-236. The structure-activity profile is discussed in terms of potential interactions in the NNRTI pocket as suggested by a docking model using AutoDock, which have a bearing on the bifunctional drug design.     

Cyclin D1 gene amplification in proliferating haemangioma

Cyclin D1 gene amplification has been reported to promote abnormal endothelial cell proliferation and angiogenesis; these findings constantly present in proliferating haemangiomas. The present study was conducted to evaluate cyclin D1 gene amplification by fluorescence in situ hybridization analysis in tissue biopsies of 22 proliferating haemangiomas from 20 infants. Two significant correlations of cyclin D1 gene amplification with the early onset and the duplication of proliferating haemangiomas have been observed. Moreover, a significant correlation (P≤0.05) has been found between the treatment parameters of proliferating haemangiomas with the amplified versus the normal cyclin D1 gene. Proliferating haemangiomas with the amplified cyclin D1 gene required more frequent flashlamp pulsed dye laser treatment sessions at the maximum dosimetry and more frequent intralesional steroid injections at the maximum dose/injection but treatment outcomes were limited. The more frequent post-treatment complications among proliferating haemangiomas with cyclin D1 gene amplification might be attributable not only to the associated more aggressive natural course, but also to the higher treatment parameters needed for effective treatment. Within the limitations of the present study, cyclin D1 gene amplification was seen for the first time in proliferating haemangiomas. We have found that the amplification of the cyclin D1 gene can predict the more aggressive natural course of proliferating haemangiomas and the limited outcome and higher incidence of complications after non–excision treatment modalities. The present findings reflect the possible usefulness of antisense cyclin D1 to improve the therapeutic outcome of proliferating haemangiomas.     

Characterization of integrons and antimicrobial resistance genes in clinical isolates of Gram-negative bacteria from Palestinian hospitals

Sixty Gram-negative bacterial isolates were collected from Palestinian hospitals in 2006. Thirty-two (53.3%) isolates showed multidrug resistance phenotypes. PCR and DNA sequencing were used to characterize integrons and antimicrobial resistance genes. PCR screening showed that 19 (31.7%) and five (8.3%) isolates were positive for class 1 and class 2 integrons, respectively. DNA-sequencing results for the captured antimicrobial resistance gene cassettes within class 1 integrons identified the following genes: dihydrofolate reductases, dfrA1 , dfrA5 , dfrA7 , dfrA12, dfrA17 and dfrA25 ; aminoglycoside adenyltransferases, aadA1, aadA2 , aadA5, aadA12 and aadB ; aminoglycoside acetyltransferase, aac(6')-Ib ; and chloramphenicol resistance gene, cmlA1 . ESBL were identified in 25 (41.7%) isolates. The identified ESBL were bla _CTX-M-15, bla _CTX-M-56, bla _OXA-1, bla _SHV-1, bla _SHV-12, bla _SHV-32 and bla _TEM-1 genes. Moreover, we characterized the plasmid-mediated quinolone resistance genes, aac(6')-Ib-cr and qnrB2 , which were detected in seven (11.7%) and two (3.3%) isolates, respectively. In this study various types of antibiotic resistance genes have been identified in Gram-negative bacteria from Palestinian hospitals, many of which are reported in the Middle East area for the first time.     

3-Keto-22-epi-28-nor-cathasterone, a brassinosteroid-related metabolite from Cystoseira myrica

Bioassay-guided purification of an ethanolic extract of Cystoseira myrica against HEPG-2 (liver) and HCT116 (colon) human cancer cell lines led to the isolation of 3-keto-22-epi-28-nor-cathasterone, 1 and cholest-4-ene-3,6-dione, 2. This finding allowed us to report for the first time that a brassinosteroid-related metabolite occurs in seaweed. These compounds showed activity in the range of 12.38–1.16 μM with selective activity of compound 2 to liver cancer cell lines.     

Blood parasites of livestock in certain Regions in Saudi Arabia

Blood samples from camels, sheep, goats and cattle from six Regions in Saudi Arabia were examined for blood parasites. Asir Region camels were disinfected while those of the Eastern, Jazan, Northern Frontiers, Riyadh and Tabouk Regions were infected with Trypanosoma evansi (5–40%), those of Riyadh and the Eastern Regions were infected with Dipetalonema evansi (1–6%) and those of the Eastern, Jazan and Riyadh Regions were infected with Eperythrozoon species (8–20%). Sheep and goats of all tested regions were infected with Theilaria hirci (4–20% and 6–14%, respectively), Theilaria ovis (5–19% and 6–24%, respectively) and Eperthrozoon ovis (2–9% and 2–8%, respectively). Sheep of the Eastern and Northern Frontiers Regions were also infected with Anaplasma ovis (2%) and also those of the Eastern Region were infected with Babesia motasi (4%) as well. Cattle of Asir and Eastern Regions were infected with Anaplasma marginale (1–3.4%) and those of the Eastern, Jazan and Riyadh Regions were infected with Theileria annulata (11.3–25%) and Eperthrozoon wenyoni (1–4%). Moreover, Jazan cattle were infected with Babesia bigemina (6%) and a benign Theileria species (27%). Some of these parasites are recorded in new localities indicating that they are spreading in the country. Also, this is the first report in Saudi Arabia of D. evansi in camels, A. ovis and B. motasi in sheep and A. marginale and B. bigemina in cattle. These parasites may be introduced into the country with infected livestock infested with the vectors of these parasites. The suspected vectors of the detected parasites in Saudi Arabia is discussed. Follow up surveys of blood parasites are recommended to assess their distribution and infection rates in the livestock of all Regions of Saudi Arabia, to make plans for control measures against their vectors.     

Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide

All-trans retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive and chemotherapeutic agents but their utility has been hampered by dose-limiting side effects. The glucuronide derivatives of 4-HPR, the oxygen-linked 4-HPROG and the carbon-linked 4-HPRCG, have been found to be more effective agents. The synthetic route to the fully C-linked analogue of 4-HPROG (4-HBRCG), which employs Suzuki coupling and Umpolung chemistries as key methodologies, is shown. The results of this study show 4-HBRCG to be an effective chemotherapeutic agent in a rat mammary tumor model while being devoid of classical retinoid toxicities.