No abstract

A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA topoisomerase II, a basic unsubstituted 4 beta-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.

A series of C-4 hydroxylated and halogenated anilino derivatives of epipodophyllotoxin or 4'-demethylepipodophyllotoxin have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 11-17 and 22 are more potent than etoposide in causing DNA breakage, while compounds 11-13, 15, 16, and 20 are as active or more active than etoposide in their inhibition of the human DNA topoisomerase II. The cytotoxicity in KB cells appears to have no direct correlation with their ability to inhibit DNA topoisomerase II and to cause protein-linked DNA breaks in cells.

This paper presents the results of axial load tests performed on instrumented model piles pre-installed in a large-scale, half-circular chamber with a viewing window in its flat-side wall. Uniform silica sand samples were prepared with different densities using dry pluviation. The effects of pile surface roughness and soil density on the response of the soil during loading of the model piles were studied by analysing sequences of digital images using the digital image correlation technique. Test results show that the extent of the zone next to the pile that is affected by loading of the pile increases as the pile surface roughness and soil density increase. The development of a shear band next to the pile shaft was also studied by carefully analysing images taken with a digital microscope during loading of the model piles. The average thickness of the shear band is in the 3·2D50–4·2D50 range for rough model piles, whereas no shear band was observed for smooth model piles. Understanding of shear band formation along the pile–soil interface provides insights into the calculation of the shaft resistance of the pile as a function of initial soil density and stress as well as pile surface roughness.

It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell. In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity. Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14. A 4 beta-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.

No abstract

Dysregulation of SUMO-specific protease 1 (SENP1) expression has been reported in several kinds of cancer, including human colorectal and prostate cancers, proposing SENP1 as an oncogene with a critical role in cancer progression. miR-133a-3p has been reported as a tumor suppressor in several malignant neoplasias. However, the precise molecular mechanisms underlying its role in colorectal cancer remain largely unknown. The aim of this work was to investigate the relationship between miR-133a-3p and SENP1 in colorectal cancer cells. We found that miR-133a-3p expression was downregulated in colorectal cancer tissues. In silico analyses indicated that SENP1 is one of the target genes of miR-133a-3p. Overexpression of miR-133a-3p mimics was able to inhibit cell growth with G1 arrest of colorectal cancer cells. Overexpression of miR-133a-3p antisense promoted cell growth of colorectal cancer cells. The luciferase reporter experiments showed that miR-133a-3p regulated the expression of SENP1 by combining with its 3'-UTR and resulted in downregulation of SENP1 and upregulation of CDK inhibitors such as p16, p19, p21, and p27. These results suggest that the miR-133a-3p-SENP1 axis might play a role in cell proliferation and cell cycle regulation of colorectal cancer cells.

A full-scale, double-wall, open-ended pipe pile with a diameter, B = 660 mm was densely instrumented with a combination of electrical-resistance and vibrating-wire strain gauges. The test pile was driven into a gravelly sand soil profile to a depth of 30·48 m and then statically and dynamically load tested. The double-wall instrumentation allows independent measurements of the outer shaft, inner shaft (plug) and annulus resistances during a static load test. The residual loads locked in the pile after driving were measured and considered in the correction of the resistance components. The load–settlement curve, load transfer curves and the profile of the unit limit shaft resistance were obtained from the static load test measurements. Two cone penetration test-based methods were used to estimate the resistance of the test pile, which was compared with that obtained from the static load test. Both methods provide good estimates for the unit shaft resistance in sandy layers with low gravel content (<20%), but significantly overestimate the unit shaft resistance mobilised in soil with high gravel content (>30%). The estimated base resistances by both methods match well that measured in the static load test.