Biomedical subjects

L B Hendry

Publications and source records attributed to L B Hendry.

At least 19 recordsLinked to original sources

PubMed2005

The influence of N-dialkyl and other cationic substituents on DNA intercalation and genotoxicity.

DNA intercalation by small chemical molecules can result in frameshift mutagenesis and chromosomal breakage. With evidence mounting that broadly diverse structures are capable of intercalating between DNA base pairs, it becomes important to better define those structural features that enhance intercalation strength and those that confer genotoxicity particularly among those intercalators that do not have the classical planar tricyclic fused ring structure. A chemical substituent that is present on many pharmaceutical and other biologically active molecules is the N-dialkyl group. In the present study, we investigate if and how the presence of an aromatic N-dialkyl or other cationic group affects the genotoxicity and DNA intercalation ability of 26 selected acridines, phenothiazines, benzophenones, triphenylethylenes and other classes of molecules. The data were obtained from the literature, from experiments using a cell-based DNA intercalation assay, and from modeling studies using a three-dimensional computational DNA docking program. It is demonstrated that cationic substitution can enhance both genotoxicity and electrostatic interactions within a chemical/DNA intercalation complex.

Animals↗

PubMed2001

Young people in 'drinking' societies? Norwegian, Scottish and Swedish adolescents' perceptions of alcohol use.

The paper studies young people's reported drinking behaviors and their views on various social aspects of alcohol, utilizing a sample of over 4000 rural adolescents aged 11.8-16.5 years in Norway, Scotland and Sweden. The methodology employed includes a common questionnaire and a range of varying qualitative approaches (essays and focus group interviews). The various venues and drinking contexts used by young people, their motives for drinking, and their 'learning' experiences with alcohol are described. Beyond nationality, the most powerful predictors of 'high' drinking are 'involvement with friends' and 'participation in commercial leisure'. The predictors for 'low' drinking are 'involvement in activities with parents' and 'parental concerns about drinking'. Results show that Scottish teenagers drink most, Norwegians least and no differences in the predictor variables are found that can explain this. Results are discussed in relation to social and cultural differences, and illustrated by quotations from rural young people in Scotland and Sweden.

Adolescent↗

PubMed2000

Novel piperidinedione analogs as inhibitors of breast cancer cell growth.

We previously reported the utility of antineoplaston-A10 (3-phenylacetylamino-2,6-piperidinedione) as an endogenous cancer protector and immune modulator in breast cancer patients (Cancer Lett., 2000, 157, 57). In this study, four new piperidinedione A10 analogs were synthesized and tested for their antimitotic activity on a human breast cancer cell line against the prototype A10 and the antibreast cancer drug tamoxifen. Moreover, the DNA binding capacity of such compounds was evaluated against A10, (E)-3-(4-Nitrocinnamoylamino)-2,6-piperidinedione "3B" and (E)-3-(4-hydroxycinnamoylamino)-2,6-piperidinedione "3D" were several-fold more potent antiproliferative agents than A10 and tamoxifen. They also had significantly higher capacity to bind DNA than A10. Conversely, (E)-3-(cinnamoylamino)-2,6-piperidinedione "3A" and (E)-3-(4-methoxycinnamoylamino)-2,6-piperidinedione) "3C" had weaker biological profiles than the lead compound A10. Detailed synthetic, spectroscopic, and biological data are reported.

Adjuvants, Immunologic↗

PubMed2000

Social relationships and health: the meaning of social "connectedness" and how it relates to health concerns for rural Scottish adolescents.

Adolescence has been posited as an important period for the onset of mental health problems and for the need to adapt successfully to many psychosocial changes. The assumption has been made that social belonging is both a health-related goal and an antidote for other sorts of emotional crises, but there is little research on how normal adolescents themselves view connections between social relationships and their physical and mental health. This qualitative study examines how social connectedness represents both a content and process variable in northern Scottish young people's discussion of their health concerns, that is, it was both a source of distress and implicated as a helpful or harmful factor in relation to other health concerns. Analyses revealed both the potency of all of these concerns and participants' belief that skills acquired now could affect their future life goals and health. Suggestions are given for building new approaches for conceptualizing rural young people's health problems and helping them cope with the social contexts involved within and around them.

Adaptation, Psychological↗

PubMed1999

Multidimensional screening and design of pharmaceuticals by using endocrine pharmacophores.

A novel computational technology derived from gene structure has been developed for screening, selecting, and designing pharmaceutical candidates. Pharmacophores, or three-dimensional molecular blueprints, were created by docking known active structures into specific sites in partially unwound DNA. The pharmacophores are composites of the van der Waals surfaces and hydrogen bonding functional groups of active molecules. Once created, molecules can be inserted into the pharmacophores and degree of fit quantitated by the volume of the molecule that fits within the composite surface and the magnitude of electrostatic interactions with charged atoms on the pharmacophore. Here, we describe endocrine pharmacophores and in particular the estrogen pharmacophore derived by docking active ligands into partially unwound DNA. Fit of candidate structures into the estrogen pharmacophore correlated with estrogenic (uterotropic) activity. For example, the super active estrogens moxestrol and 11beta-acetoxyestradiol fit better within the site than estradiol. Bisphenol A, a putative endocrine disrupter with suspected estrogenic activity, was a poor fit in the pharmacophore. Consistent with this prediction, bisphenol A was recently shown to lack uterotropic activity. The capacity of the endocrine pharmacophores to predict certain nontarget activities was demonstrated by using the antiandrogen cyproterone acetate that did not fit the estrogen or thyroid pharmacophores but fit partially into the progestin and glucocorticoid pharmacophores. Cyproterone acetate has been reported to have weak progestational and glucocorticoid activities. The pharmacophores provide for the first time a multidimensional computational method that can simultaneously predict multiple activities of diverse molecular structures.

Drug Design↗

PubMed1998

The ligand insertion hypothesis in the genomic action of steroid hormones.

Gene regulation by steroids is tightly coupled to hormone concentration and stereochemistry. A key step is binding of hormones to receptors which interact with consensus DNA sequences known as hormone response elements (HREs). The specificity and strength of hormone binding do not correlate well with hormonal activity suggesting an additional step involving recognition of ligand by the gene. Stereospecific fit of hormones between base pairs and correlation of fit with hormonal activity led to the proposal that such recognition involves insertion of hormone into DNA. Here, the feasibility of insertion was investigated using computer models of the glucocorticoid receptor DNA binding domain bound to its HRE. The site reported to accommodate glucocorticoids was found in the HRE and was exposed to permit unwinding at this locus. The resulting cavity in the unwound DNA/receptor interface fit cortisol remarkably well; cortisol formed hydrogen bonds to both the receptor and DNA. Current experimental evidence is generally consistent with ligand binding domains of receptors undergoing a conformational change which facilitates transfer of the ligand into the unwound DNA/receptor interface. We propose this step is rate limiting and alterations in receptor, DNA or hormone which attenuate insertion impair hormonal regulation of gene function.

Computer Simulation↗

PubMed1996

Diverse modes of action of progesterone and its metabolites.

Progesterone and its metabolites have a variety of diverse effects in the brain, uterus, smooth muscle, sperm and the oocyte. The effects include changes in electrophysiological excitability, induction of anesthesia, regulation of gonadotropin secretion, regulation of estrogen receptors, modulation of uterine contractility and induction of acrosome reaction and oocyte maturation. The latency of the effects vary from several seconds to several hours. Thus, it is not surprising that multiple mechanisms of action are involved. The classical mechanism of steroid hormone action of intracellular receptor binding has been supplemented by the possibility of the steroid acting as a transcription factor after the binding of the receptor protein to DNA. Other mechanisms include influence of the steroids on membrane fluidity and acting through other cell signalling systems, membrane receptors and GABA(A) receptors. Of particular interest are multiple mechanisms for the same types of action. For example the effect of progesterone on gonadotropin release is largely exerted via the classical intracellular receptor as well as membrane receptors, whereas 3(alpha),5(alpha)-tetrahydroprogesterone-induced LH release occurs via the GABA(A) receptor system. The inhibition of uterine contractility by progesterone is regulated by progesterone receptors while the action of 3(alpha),5(alpha)-tetrahydroprogesterone on uterine contractility is regulated by GABA(A) receptors. The regulation of the differences in the pattern of progesterone effects on estrogen receptor dynamics in the anterior pituitary and the uterus in the same animal are also of considerable interest.

Animals↗

PubMed1995

Emerging diversities in the mechanism of action of steroid hormones.

The classical genomic action of steroid hormones acting through intracellular receptors is well recognized. Within this concept of action, questions regarding the ultimate fate of the hormone and lack of a tight correlation between tissue uptake and biological activity with receptor binding remain unanswered. Evidence has accumulated that steroid hormones can exert non-classical action that is characterized by rapid effect of short duration. In most of these cases, the hormone effects occurs at the membrane level and is not associated with entry into the cell. The possible mechanisms for these non-classical actions are: (a) changes in membrane fluidity; (b) steroid hormone acting on receptors on plasma membranes; (c) steroid hormones regulating GABAA receptors on plasma membranes; and (d) activation of steroid receptors by factors such as EGF, IGF-1 and dopamine. Data have also been obtained indicating that receptor-mediated insertion of steroid hormones into DNA may take place with the steroid acting as a transcription factor. These new proposed mechanism of action of steroid hormones should not be viewed as a challenge to the classical mechanism. These diverse modes of action provide for an integrated action of hormones which may be rapid and of short duration or prolonged to address the physiological needs of the individual.

Androgens↗

PubMed1995

A putative step in steroid hormone action involves insertion of steroid ligands into DNA facilitated by receptor proteins.

The hypothesis is advanced that hormonal ligands in the steroid/thyroid superfamily act through insertion between base pairs in partially unwound DNA. Using published X-ray coordinates of the complex of the glucocorticoid hormone response element (GRE) with the glucocorticoid receptor DNA binding domain, the interface between the protein and the gene was examined. The site 5'-TG-3'-5'-CA-3' previously shown to accommodate cortisol was found in the first two bases of the GRE half sites, 5'-TGTTCT-3'. These base pairs were sufficiently exposed at the receptor-gene interface to permit access by the steroid. Docking of cortisol into the receptor/DNA complex resulted in a favorable van der Waals energy. Given the general lack of correlation of receptor binding with hormonal activity, we propose that hormone action involves an additional step in which the receptor protein in concert with other transcription factors inserts the hormone into the DNA. This notion provides an explanation for earlier paradoxical observations including structural analogies between base pairs and steroid hormones. The insertion hypothesis suggests that receptor bound ligand facilitates DNA unwinding, stereospecific control of donor/acceptor functional groups on the DNA followed by insertion and release of the ligand between base pairs at 5'-TG-3'-5'-CA-3'.

Amino Acid Sequence↗

PubMed1994

Hypoglycemia caused by selegiline, an antiparkinsonian drug: can such side effects be predicted?

Treatment with selegiline produced profound hypoglycemia in a 70-year-old man with Parkinson's disease. The hypoglycemia was accompanied by hyperinsulinemia and persisted for 1 week after selegiline was discontinued. Although this side effect of antidepressant monoamine oxidase inhibitors was well documented in 1959-1968 publications, it was not known to the manufacturer of selegiline. Effects of drugs on glucose metabolism may be predictable through a novel molecular modeling technique developed in our laboratories, which shows that glucose exhibits stereochemical complementarity to a specific site in partially unwound DNA. Selegiline and other molecules affecting glucose metabolism fit into the same DNA base sequence. It therefore should be possible to employ this technique to identify pharmaceutical agents that possess hypoglycemic or hyperglycemic effects in vivo.

Aged↗

PubMed1994

Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes.

Drug design technology based upon DNA stereochemistry and now supplemented by computer modeling was used to design a novel compound to inhibit estrogen-induced tumor cell growth. A known compound 3-phenylacetylamino-2,6-piperidinedione (PP) was accommodated in partially unwound DNA in a manner consistent with criteria for antiestrogens. Examination of the PP-DNA complex revealed that substitution of a hydroxyl group at the para position (p-OH-PP) would provide a stereospecific hydrogen bond and a substantial increase in fit as assessed by energy calculations. The antiestrogen tamoxifen could also be accomodated within the site; analogous substitution of a hydroxyl at the 4 position resulted in a better fitting molecule. 4-Hydroxytamoxifen is a more potent antiestrogen than tamoxifen. Synthesis and subsequent evaluation of p-OH-PP as an inhibitor of estrogen stimulated MCF-7 (E3) human breast cancer cell growth demonstrated that p-OH-PP was more active than both PP and its hydrolysis product phenylacetylglutamine. As predicted, the order of fit into DNA correlated with the relative ability to inhibit estrogen-induced growth of tumor cells suggesting that the evolving drug design technology will be valuable in developing new drugs for breast cancer.

Benzeneacetamides↗

PubMed1994

Design of novel antiestrogens.

The physicochemical principle of "die and coin" complementarity proffered by Pauling and Delbruck and exemplified in Watson and Crick DNA was used to design new antineoplastic compounds. In search of an explanation for why certain molecules and not others are present in nature, biologically active small molecules were discovered to exhibit complementarity when inserted into cavities between base pairs in DNA. Ligands in the steroid/thyroid hormone/vitamin D family fit particularly well into the site 5'-dTdG-3'.5'-dCdA-3'. Degree of fit of various candidate compounds in the manner of a given hormone correlated with degree of hormonal activity. Hormone antagonists fit into the same site but in a different manner than the agonists. Computer graphics and energy calculations confirmed salient observations including the remarkable complementarity of estradiol and DNA. Using the above criteria, a new candidate antiestrogen, para-hydroxyphenyl-acetylamino-2,6-piperidinedione was successfully designed. Taken as a whole, these results coupled with recent independent findings raise the possibility that the mode of action of certain hormones and hormone antagonists may involve direct insertion into DNA mediated by classical protein receptors and other transcription factors.

Animals↗

PubMed1993

Drug design with a new type of molecular modeling based on stereochemical complementarity to gene structure.

Why certain chemical structures and not others are present in nature has been a recurring question raised by scientists since the first organic natural products were characterized. Of equal interest has been elucidating what structural features within any given class of organic molecules are responsible for biological activity. Historically, the lack of satisfactory answers to both questions has relegated the development of biologically active molecules either to serendipity or to exhaustive synthesis and biological testing of large numbers of compounds. This frustration is particularly evident in the pharmaceutical industry where the development of drug agonists and antagonists is often time consuming, tedious and expensive. Fortunately, this picture is beginning to change as more information is derived from modern molecular modeling techniques including characterization of the active sites in enzymes and the ligand binding sites in receptors. Over the past 15 years another approach has emerged based upon a series of discoveries made in our laboratories with molecular models. Namely, many biologically active small molecules have been found to possess complementary stereochemical relationships with gene structure. These relationships have proven useful in understanding constraints imposed by nature on the structures of small molecules and in correlating structure with activity among certain classes of compounds. Recently, computer graphics and energy calculations have confirmed salient observations lending credence to what promises to be a powerful and rapidly evolving technology for designing new safe and effective drugs.

Animals↗

PubMed1993

Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its para-hydroxy analog.

3-Phenylactetylamino-2,6-piperidinedione (A10) inhibited estradiol stimulated cell growth in the MCF-7 (E3) human breast tumor cell line in vivo and in vitro. While high concentrations of A10 were needed to inhibit cell proliferation (IC50 = 3 x 10(-3) M in vitro), the compound demonstrated little toxicity. The effect appeared specific since a hydrolysis product of A10, phenylacetylglutamine, demonstrated no growth inhibitory activity at similar concentrations in MCF-7 (E3) cells in vitro. A computer designed analog, p-hydroxy A10, was more potent than A10 in inhibiting activity in MCF-7 (E3) cells in vitro. The IC50 for p-hydroxy A10 was 7 x 10(-6) M which was comparable to that of the antiestrogen, tamoxifen (IC50 1 x 10(-7) M). All three compounds caused a decline in estrogen receptor levels in a dose-dependent fashion. A10 also inhibited estradiol induction of progesterone receptors. Examination of protein kinase activity following an acute exposure to a 10(-11) M growth stimulatory dose of estradiol revealed a 168% increase in protein kinase activity over that of untreated control cells. A10 in a dose-responsive fashion inhibited the estradiol stimulated increase in protein kinase activity. The protein kinase activity was also inhibited by p-hydroxy A10. These activities of A10 and p-hydroxy A10 coupled with the low toxicity and novelty of the basic A10 structure provide an exciting possibility of developing a new class of clinically useful antineoplastic drugs with minimal side effects.

Animals↗

PubMed1992

Computer modeling of gibberellin-DNA binding.

Computer modeling and molecular mechanics performed on the intercalation complexes of selected gibberellins or biosynthetic precursors with DNA dinucleotides revealed that under appropriate conditions the ligands insert (intercalate) between the base-paired double-stranded dinucleotide, 5'-dTdA-3'. Stabilization of the double-stranded dinucleotide after docking of a gibberellin between base pairs is inferred by the sum negative energy of hydrogen bonding and van der Waals contacts and the entropic changes which accompany the formation of each ligand-dinucleotide complex. In addition, the interactions of the gibberellins and dinucleotides, with the gibberellic acid-dinucleotide complex serving as the prototype, show optimum geometry and stereochemical hydrogen bonding recognition which are dependent upon the complementary chirality and stereochemistry of the individual components. Whether or not the gibberellins directly influence the uncoiling of DNA or gene expression at the transcriptional level via an intercalation mechanism is a matter of conjecture, albeit one that warrants intensive investigation.

Computer Simulation↗

PubMed1992

Adolescents' perceptions of significant individuals in their lives.

180 adolescents, aged 11-12 years, and 180, aged 15-16 years, from one Scottish secondary school participated in this study. The purposes of the investigation were: to determine the most significant family member and unrelated person in young peoples' lives; and to identify which characteristics rendered these persons important. 'Mother' and '(same sex) friend' emerged as the outstanding choices. Family members (except siblings) were associated with positive characteristics, whilst amongst unrelated adults, youth group leaders were viewed positively. By contrast, school teachers were primarily seen as occupying a challenging role. Where age and sex differences were found, it was invariably those in early adolescence and females who were more likely to attribute positive characteristics. These results are discussed in relation to the concept of 'mentoring' and the role of mentors in adolescents' lives.

Adolescent↗

PubMed1992

Adolescence and health inequalities: extensions to Macintyre and West.

The paper investigates class based health inequalities in mid to late adolescence. Health status is assessed by means of three subjective self-report measures; evaluation of general health, psychological well-being and disability/long-standing illness. Using six measures of social class (three occupationally and three non-occupationally based) which derive from parental characteristics, no evidence for consistent class based differentials in health amongst adolescents is found. However, it is not concluded that class based health inequalities are absent at this stage of the life cycle. Instead, it is argued that the above measures of social class differentiate between young people on the basis of the socio-economic status of their parents. As such they fail to allow for the possibility that variations in the current social position of young people themselves may have important consequences for their health. Current social position is assessed in terms of economic activity status, occupation and educational attainment. Using these measures, class based health inequalities are indeed found. Extending the analysis further, the relationship between social class of origin, current social circumstances and self-assessed health status is investigated by considering inter-generational occupational mobility. Again, evidence for class based health inequalities is found.

Adolescent↗

PubMed1992

The metabolic pathways for hormonal steroids appear to be reflected in the stereochemistry of DNA.

Computer graphics and energy calculations were employed to examine the relative fit of progesterone and its major biosynthetic precursors and inactive metabolites into partially unwound double stranded DNA. Progesterone was found to be the best fitting molecule; moreover, it was the only compound which exhibited full stereochemical complementarity by inserting completely between base pairs and forming optimal hydrogen bonds with both deoxyribose-phosphate backbones. Intermediates in each step of the biosynthetic and degradation pathways were progressively increasing and decreasing fits into DNA, respectively. When the fits of various possible stereoisomers were examined, the positions of functional groups manifest in the known biosynthetic precursors were found to provide the best possible fitting structures. Conversely, the positions of functional groups of known inactive metabolites provided the worst possible fitting structures. These findings coupled with previous reports showing that the specific biological function assigned to each class of steroid hormone correlates with the formation of a unique pattern of donor/acceptor linkages confirms that hormonal structures are indeed rare in their capacity to form "lock and key" complexes with DNA. Given that all possible linkages to DNA are not yet accounted for, the existence of other naturally occurring compounds with salient biological function is predicted.

Computer Simulation↗