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Biomedical subjects

F Lavelle

Publications and source records attributed to F Lavelle.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis and biological evaluation of O-alkylated tropolones and related alpha-ketohydroxy derivatives as ribonucleotide reductase inhibitors.

A series of O-alkylated tropolones and related alpha-ketohydroxy compounds were evaluated for their biological activities and were shown to present an expected ribonucleotide reductase inhibition and cytotoxicity against some cancer cell lines but no antitubulin activity. Pharmacomodulation studies were realised to understand and enhance the observed activities. These original benzylic, heterocyclic and allylic compounds have been synthesised by a phase-transfer catalysed O-alkylation developed in our laboratories.

Animals↗
PubMed2000

Multivariate data analysis using D-optimal designs, partial least squares, and response surface modeling: A directional approach for the analysis of farnesyltransferase inhibitors.

We have investigated the combined use of partial least squares (PLS) and statistical design principles in principal property space (PP-space), derived from principal component analysis (PCA), to analyze farnesyltransferase inhibitors in order to identify "activity trends" (an approach we call a "directional" approach) and quantitative structure-activity relationships (QSAR) for a congeneric series of inhibitors: the benzo[f]perhydroisoindole (BPHI) series. Trends observed in the PCA showed that the descriptors used were relevant to describe our structural data set by clearly identifying two well-defined structural subclasses of inhibitors. D-Optimal design techniques allowed us to define a training set for PLS study in PP-space. Models were derived for each biological assay under evaluation: the in vitro Ki-Ras and cellular HCT116 tests. Each of these assay-based sets was subdivided once more into two subsets according to two structural classes in this BPHI series as revealed by the PCA model. The response surface modeling (RSM) methodology was used for each subset, and the corresponding RSM plots helped us identify "activity trends" exploited to guide further analogue design. For more precise activity predictions more refined PLS models on constrained PP-spaces were developed for each subset. This approach was validated with predicted sets and demonstrates that useful information can be extracted from just a few very informative and representative compounds. Finally, we also showed the potential use of such a strategy at an early stage of an optimization process to extract the first "activity trends" that might support decision making and guide medicinal chemists in the initial design of new analogues and/or lead followup libraries.

Alkyl and Aryl Transferases↗
PubMed2000

Telomerase: a therapeutic target for the third millennium?

Telomerase offers the potential opportunity to control cell proliferation by interfering with a totally new and unique biological process which is cell senescence. The aim of this review is to impartially present the state of the art in telomerase with the pros and the cons of the current scientific situation of this fast-growing and fascinating topic for answering the key question asked by experimental and medical oncologists: Will telomerase be a therapeutic target for the third millenium? The most convincing argument (which is a scientifically documented one) for going ahead with this target is obviously the strong correlation existing between the level and frequency of telomerase expression and the malignant properties of tumors. This has been now largely documented in established tumor cell lines and fresh tumor samples obtained from patients. Noteworthy is the very important difference of telomerase expression between malignant and normal tissues. This difference is much higher than those observed for classical enzymatic targets of chemotherapy such as thymidylate synthetase, dihydrofolate reductase and topoisomerases. If this translates to the clinical situation, telomerase inhibitors might display a good selectivity for tumor cells with a minimal toxicity for normal tissues. The most appealing criticism (which is still purely speculative) is obviously the clinical relevance of inhibiting telomerase in cancer patients. According to the paradigm currently proposed for telomeres and telomerases, it can be predicted that telomerase inhibition will not affect a tumor until its telomeres reach the critical size for entering senescence. This means that during anti-telomerase therapy, the tumor cells will continue grow undergoing 20-30 divisions until the telomeres reach a critical size leading to tumor senescence. Does this make sense, especially in patients with advanced tumors at the beginning of the therapy? Ultimately, the definitive answer to the question will not come from intellectual speculation but from the properties of telomerase inhibitors, first in tumor bearing animals, then finally in cancer patients! Several institutions are very active in the development of telomerase inhibitors. Different stategies are used: direct inhibition of telomerase, interference with telomeres (G quartets), interaction with other proteins involved in the regulation of telomerase and telomeres.

Animals↗
PubMed2000

RPR112378 and RPR115781: two representatives of a new family of microtubule assembly inhibitors.

A screening program aimed at the discovery of new antimicrotubule agents yielded RPR112378 and RPR115781, two natural compounds extracted from the Indian plant Ottelia alismoides. We report their isolation, structural determination, and mechanisms of action. RPR112378 is an efficient inhibitor of tubulin polymerization (IC(50) = 1.2 microM) and is able to disassemble preformed microtubules. Regarding tubulin activity, RPR115781 is 5-fold less active than RPR112378. Tubulin-RPR112378 complexes, when isolated by gel filtration, were able to block further tubulin addition to growing microtubules, a mechanism that accounts for the substoichiometric effect of the drug. RPR112378 was found to prevent colchicine binding but not vinblastine binding to tubulin. Although colchicine binding is known to induce an increase of tubulin GTPase activity, no such increase was observed with RPR112378. We show that RPR112378 is a highly cytotoxic compound and that RPR115781 is 10, 000-fold less active as an inhibitor of KB cell growth. Part of the cytotoxicity of RPR112378 is probably caused by a reaction of addition with sulfhydryl groups, an observation that has not been made with RPR115781. In conclusion, these molecules represent a new class of inhibitors of microtubule assembly with potential therapeutic value.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase-1 inhibitor GGTI-298 disrupts MAP kinase activation and G(1)-S transition in Ki-Ras-overexpressing transformed adrenocortical cells.

To test the Kirsten-Ras (Ki-Ras) alternative prenylation hypothesis in malignant transformation, we used a novel farnesyltransferase inhibitor competitive to farnesyl-pyrophosphate, RPR130401, and a CaaX peptidomimetic geranylgeranyltransferase-1 inhibitor GGTI-298. In Ki-Ras-overexpressing transformed adrenocortical cells, RPR130401 at 1-10 microM inhibited very efficiently the [(3)H]farnesyl but not [(3)H]geranylgeranyl transfer to Ras. However, proliferation of these cells was only slightly sensitive to RPR130401 (IC(50)=30 microM). GGTI-298 inhibited the growth of these cells with an IC(50) of 11 microM but cell lysis was observed at 15 microM. The combination of 10 microM RPR130401 and 10 microM GGTI-298 inhibited efficiently (80%) cell proliferation. These combined inhibitors but not each inhibitor alone blocked the cell cycle in G(0)/G(1) and disrupted MAP kinase activation. Thus, combination of two inhibitors, at non-cytotoxic concentrations, acting on the farnesyl-pyrophosphate binding site of the farnesyltransferase and the CaaX binding site of the geranylgeranyltransferase-1 respectively is an efficient strategy for disrupting Ki-Ras tumorigenic cell proliferation.

Adrenal Glands↗
PubMed1999

Purification and characterization of human DNA topoisomerase IIIalpha.

Human topoisomerase IIIalpha (hTopo IIIalpha), the recently identified first member of the topoisomerase IA subfamily in humans, has a central domain which is highly homologous to the yeast topoisomerase III, but an overall organization closer to that of Escherichia coli DNA topoisomerase I. In order to determine the properties of hTopo IIIalpha, compared to those of other topoisomerase IA subfamily members, we purified this enzyme to near homogeneity, together with an active site-mutant Y337F. We show that hTopo IIIalpha is able to relax negatively supercoiled DNA in a distributive manner, leading to the total disappearance of the initial substrate and the appearance of intermediate topoisomers. This DNA relaxation activity is magnesium-dependent, although a low concentration of MgCl2is sufficient to obtain efficient catalysis. 32P-transfer experiments demonstrated that hTopo IIIalpha is able to cleave a single-stranded oligonucleotide and to bind covalently to the 5'-end of the cleaved DNA. Addition of 0.5 M NaCl reverses the reaction, leading to the religation of the oligo-nucleotide. Experiments utilizing several different single-stranded oligonucleotides permitted us to map several cleavage sites and to deduce a consensus sequence for DNA cleavage (CANNN downward arrow), which is different from that for other members of the Topo IA subfamily.

Catalysis↗
PubMed1999

Domain-structured N1,N2-derivatized hydrazines as inhibitors of ribonucleoside diphosphate reductase: redox-cycling considerations.

Eight analogues of 1-[5-halogenosalicylidene]-2-[2'-pyridinoyl]hydrazine and -[2'-pyridyl]hydrazine, four of 1-[pyridoxylidene]-2-[2'-pyridinoyl]hydrazine, seven of 1-[pyridoxylidene]-2-[2'-pyridyl]hydrazine, and one each of 1, 2-bis[pyridoxylidene]diaminoethane and bis[pyridoxylidenehydrazino]phthalazine were synthesized. Their solutions in DMF were assayed for activity against the metalloenzyme ribonucleoside diphosphate reductase (RdR), prepared from a subcutaneously growing murine tumor (sarcoma 180) implanted in B6D2F3 male mice. The 14C-labeled CDP reductase was assayed by the modified method of Takeda and Weber, in which [14C]cytidine was separated from deoxycytidine by thin-layer chromatography (TLC) on cellulose foil. Distribution of radioactivity was assessed with an automatic TLC linear analyzer. Of the 31 compounds tested, 13 were essentially inactive, 7 were highly active against RdR, and the remaining 20 were slightly more active than hydroxyurea (used as a reference compound). The mechanism of inhibition is discussed in terms of three alternative pathways, initiated by sequestration of iron embedded in the R1 subunit of the metalloenzyme to form a C-centered chelate radical (via redox cycling). Alternatively, the latter could either reduce the tyrosyl radical or intercept radicals generated in the reduction process.

Animals↗
PubMed1999

The development of telomerase inhibitors: the G-quartet approach.

Human telomeres, which consist of repeated TTAGGG sequences, have recently become the focus of intense and highly competitive biological research. This scientific interest lies in their unique biological functions: telomeres are essential for genome integrity and appear to play an important role in cellular aging and cancer. As telomerase appears to be selectively expressed in tumors versus normal cells, this enzyme represents a good target for inhibition. Different types of telomerase inhibitors have recently been described. We will present briefly the different strategies that have been proposed to achieve efficient telomerase inhibition, with a special emphasis on G-quartet ligands.

Enzyme Inhibitors↗
PubMed1998

[Preclinical evaluation of anticancer drugs: a model remaining a model!].

Two criteria are firstly used in the selection of new anticancer agents:--originality of the mechanism of action and significant experimental antitumor activity in an in vivo animal model. Murine tumors grafted in syngenic mice and human tumor xenografts implanted in nude mice are old models which continue to be widely used. Such models are useful but have the tendency to select many false positives (compounds active in mice but inactive in patients). This discrepancy can be explained by differences due to biological materials and also to the methodologies used in laboratories and clinic. Such models will certainly continue to play a major role in the future but they will have to be used in conditions more relevant for clinical extrapolation. Transgenic mice developing in situ tumors constitute new innovative models for in vivo evaluation of anticancer agents. Finally, a putative new class of antitumor agents emerges with the signal transduction modulators: such compounds have antitumor and toxicological properties very different from those of conventional chemotherapeutic agents. If the first representatives prove to be useful in clinic, rules for toxicology, preclinical and clinical evaluation will have to be changed.

Animals↗