Ellipticine analogues and related compounds as inhibitors of reverse transcriptase and as inhibitors of the efflux pump.

Ten polycyclic derivatives related to ellipticine have been synthesised and tested for their intercalating, reverse transcriptase (RT) inhibitory and multidrug resistance efflux pump inhibitory properties. The intercalating activity and the RT inhibitory activity of the derivatives suggest that ellipticine analogues bind at an allosteric binding site on RT or that this inhibition could be controlled at the DNA level. The MDR efflux pump inhibitory activities of these derivatives, however, appears to be unrelated to the DNA binding ability.

The inhibition of SOS-responses and MDR by phenothiazine-metal complexes.

The gene of multidrug resistance (mdr) is inducible by different environmental stresses (SOS gene). We tested the inhibitory action of some new metal complexes of phenothiazines on megacin encoding bacterial gene induced by mitomycin-C as an example of "SOS induction" and on efflux pump of mouse lymphoma cells. The interaction of compounds to DNA was measured by thermal stability of DNA. It was found that metal co-ordination complexes of trifluoperazine (TFP) and chlorpromazine (CPZ) added before mitomycin administration have an inhibitory action on megacine induction. The TFP-V(IV) complex was effective at a lower concentration than TFP alone. The inhibitory effect of some metal coordinating complexes (TFP-Cu(II) and TFP- V(IV)) exceeded the action of TFP alone on efflux pumps. We propose that these compounds can form a complex with the regulatory protein or DNA resulting in the inhibition of SOS response and inhibit the mdr function by inactivating the P-glycoprotein as well.

Late-onset idiopathic scoliosis in children six to fourteen years old. A cross-sectional prevalence study.

We performed a point-prevalence survey of 15,799 children, six to fourteen years old, who formed part of a prospective longitudinal study. Our purpose was to detect the prevalence of scoliosis and to investigate associated factors. On the basis of the initial screening, 934 children (5.9 per cent) were referred for additional clinical and radiographic examinations; 896 children returned for this second evaluation. A lateral spinal curve with a Cobb angle of more than 5 degrees was seen in 431 children (2.7 per cent of the 15,799 children). Only seventy-six children (0.5 per cent) had a curve that met our definition of idiopathic scoliosis (a curve of more than 10 degrees with concordant apical rotation). The point-prevalence rate was higher in girls, and it increased with age. The rate was 0.1 per cent (four of 5246) in the age-group of six to eight years, 0.3 per cent (sixteen of 5831) in the age-group of nine to eleven years, and 1.2 per cent (fifty-six of 4722) in the age-group of twelve to fourteen years old. With allowance for the fact that different definitions of idiopathic scoliosis have been used in earlier studies, our results suggest that the natural history of idiopathic scoliosis may be becoming more benign spontaneously.

Potential antitumour agents. Synthesis, DNA binding studies and biological activity of 9-aminoacridinyl derivatives of citrulline and arginine.

The synthesis and characterisation of the 9-acridinyl derivatives of citrulline and arginine are reported together with studies on the intercalation of these compounds into DNA. The antitumour activity of these compounds in vitro against two cell lines is also reported.

Preparation and evaluation of 2-substituted anthraquinones based on the anthracyclines.

Anthraquinones substituted at the 2 position with a basic side chain were prepared, and their binding to DNA was evaluated. All compounds showed an intercalative mode of binding to DNA; 1,4-dihydroxy derivatives bound more strongly than 1-hydroxy or nonhydroxylated compounds. Greatest DNA-binding activity was found where there were five atoms between the anthraquinone ring and the basic nitrogen.