Antiproliferative and phenotype-transforming antitumor agents derived from cysteine

Selective destruction of malignant tumor cells without damaging normal cells is an important goal for cancer chemotherapy in the 21st century. Differentiating agents that transform cancer cells to either a nonproliferating or normal phenotype could potentially be tissue-specific and avoid side effects of current drugs. However, most compounds that are presently known to differentiate cancer cells are histone deacetylase inhibitors that are of low potency or suffer from low bioavailability, rapid metabolism, reversible differentiation, and nonselectivity for cancer cells over normal cells. Here we describe 36 nonpeptidic compounds derived from a simple cysteine scaffold, fused at the C-terminus to benzylamine, at the N-terminus to a small library of carboxylic acids, and at the S-terminus to 4-butanoyl hydroxamate. Six compounds were cytotoxic at nanomolar concentrations against a particularly aggressive human melanoma cell line (MM96L), four compounds showed selectivities of greater than or equal to5:1 for human melanoma over normal human cells (NFF), and four of the most potent compounds were further tested and found to be cytotoxic for six other human cancer cell lines (melanomas SK-MEL-28, DO4; prostate DU145; breast MCF-7; ovarian JAM, CI80-13S). The most active compounds typically caused hyperacetylation of histones, induced p21 expression, and reverted phenotype of surviving tumor cells to a normal morphology. Only one compound was given orally at 5 mg/kg to healthy rats to look for bioavailaiblity, and it showed reasonably high levels in plasma (C-max 6 mug/mL, T-max 15 min) for at least 4 h. Results are sufficiently promising to support further work on refining this and related classes of compounds to an orally active, more tumor-selective, antitumor drug.

Marine bioprospecting - Trawling for treasure and pleasure

This Microreview seeks to highlight the molecular diversity present in marine organisms, and illustrate by example some of the challenges encountered in exploring this resource. Marine natural products exhibit an impressive array of structural motifs, many of which are derived from biosynthetic pathways that are uniquely marine, Most importantly some marine metabolites possess noteworthy biological activities, activities that have potential application outside marine ecosystems, such as antibiotics, antiparasitics, anticancer agents etc... The isolation, spectroscopic characterisation and assignment of stereostructures to these unusual metabolites is both challenging and rewarding. Examples featured in this Microreview follow a common theme in that they are all recent accounts of the isolation of natural products from Australian marine sponges, carried out in the laboratories of the author. In addition to presenting brief comments on specific structure elucidation strategies, an effort is made to emphasize techniques for solving stereochemical issues, as well as to speculate on the biosynthetic origins of some of these exotic marine natural products.

Lipophilic methotrexate conjugates with glucose-lipoamino acid moieties: Synthesis and in vitro antitumor activity

To obtain methotrexate (MTX) derivatives with a balanced hydrolipophilic character, we synthesized a series of conjugates in which the drug was linked to lipoamino acid (LAA)-glucose residues (LAAG-MTX). These conjugates displayed increased solubility in polar media compared with the corresponding LAA-MTX conjugates previously described. In vitro biological testing of LAAG-MTX indicated that the introduction of the sugar moiety decreased the biological activity of these MTX conjugates. The tetradecyl derivative 6b, however, was effective in inhibiting the dihydrofolate reductase activity in vitro and showed an inhibitory effect on human lymphoblastoid cell growth. (C) 2001 Wiley-Liss, Inc.

Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity

There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.

A Fibred Tableau Calculus for Modal Logics of Agents

In previous works we showed how to combine propositional multimodal logics using Gabbay's \emph{fibring} methodology. In this paper we extend the above mentioned works by providing a tableau-based proof technique for the combined/fibred logics. To achieve this end we first make a comparison between two types of tableau proof systems, (\emph{graph} $\&$ \emph{path}), with the help of a scenario (The Friend's Puzzle). Having done that we show how to uniformly construct a tableau calculus for the combined logic using Governatori's labelled tableau system \KEM. We conclude with a discussion on \KEM's features.

BIO Logical Agents: Norms, Beliefs, Intentions in Defeasible Logic

In this paper we follow the BOID (Belief, Obligation, Intention, Desire) architecture to describe agents and agent types in Defeasible Logic. We argue, in particular, that the introduction of obligations can provide a new reading of the concepts of intention and intentionality. Then we examine the notion of social agent (i.e., an agent where obligations prevail over intentions) and discuss some computational and philosophical issues related to it. We show that the notion of social agent either requires more complex computations or has some philosophical drawbacks.

Interaction between Normative Systems and Cognitive Agents in Temporal Modal Defeasible Logic

While some recent frameworks on cognitive agents addressed the combination of mental attitudes with deontic concepts, they commonly ignore the representation of time. An exception is [1]that manages also some temporal aspects both with respect to cognition and normative provisions. We propose in this paper an extension of the logic presented in [1]with temporal intervals.

Contextual Deliberation of Cognitive Agents in Defeasible Logic

This article extends Defeasible Logic to deal with the contextual deliberation process of cognitive agents. First, we introduce meta-rules to reason with rules. Meta-rules are rules that have as a consequent rules for motivational components, such as obligations, intentions and desires. In other words, they include nested rules. Second, we introduce explicit preferences among rules. They deal with complex structures where nested rules can be involved.

Synthesis of hydroperoxide and perketal derivatives of polyunsaturated fatty acids as potential antimalarial agents

Hydroperoxide derivatives of beta-oxa-substituted polyunsaturated fatty acids were prepared by 15-lipoxygenase catalysed oxidation and perketal derivatives of fatty acid hydroperoxides were synthesized. The perketals are more stable than their parent fatty acid hydroperoxides, but less active as antimalarial agents in the in vitro growth inhibition of Plasmodium falciparum. (C) 1998 Elsevier Science Ltd. All rights reserved.

Th2-type CD4(+) cells neither enhance nor suppress antitumor CTL activity in a mouse tumor model

Many cervical cancers express the E7 protein of human papillomavirus 16 as a tumor-specific Ag (TSA). To establish the role of E7-specific T cell help in CD8(+) CTL-mediated tumor regression, C57BL/6J mice were immunized with E7 protein or with a peptide (GF001) comprising a minimal CTL epitope of E7, together with different adjuvants, Immunized mice were challenged with an E7-expressing tumor cell line, EL4.E7. Growth of EL4.E7 was reduced following immunization with E7 and Quil-A (an adjuvant that induced a Th1-type response to E7) or with GF001 and Quil-A, Depletion of CD8(+) cells, but not CD4(+) cells, from an immunized animal abrogated protection, confirming that E7-specific CTL are necessary and sufficient for TSA-specific protection in this model. Immunization with E7 and Algammulin (an alum-based adjuvant) induced a Th2-like response and provided; no tumor protection. To investigate whether a Th2 T helper response to E7 could prevent the development of an E7-specific CTL-mediated protection, mice were simultaneously immunized with E7/Algammulin and GF001/Quil-A or, alternatively, were immunized with GF011/Quil-A 8 wk after immunization with E7/Algammulin, Tumor protection was observed in each case. We conclude that an established Th2 response to a TSA does not prevent the development of TSA-specific tumor protective CTL.

The lobatamides, novel cytotoxic macrolides from southwestern Pacific tunicates

Novel macrolides, lobatamides A-F (1-6), have been isolated from shallow water Australian collections of Aplidium lobatum, from a deep water collection of Aplidium sp., and from an unidentified Philippine ascidian. Full details of the isolation and structure elucidation of 1-6 are provided herein, along with results and analyses of the testing of lobatamides A-D (1-4) in the NCI human tumor 60 cell-line screen. The lobatamides share a common core structure with the recently described salicylihalamides, which were isolated from a Haliclona sp. sponge. COMPARE analyses of the mean-graph differential cytotoxicity profiles of the lobatamides and the salicylihalamides showed high correlations with each other but not with members of the NCI's standard agents database. These compounds, therefore, appear to comprise a new mechanistic class, meriting further antitumor investigations.

Optimal release strategies for biological control agents: an application of stochastic dynamic programming to population management

1. Establishing biological control agents in the field is a major step in any classical biocontrol programme, yet there are few general guidelines to help the practitioner decide what factors might enhance the establishment of such agents. 2. A stochastic dynamic programming (SDP) approach, linked to a metapopulation model, was used to find optimal release strategies (number and size of releases), given constraints on time and the number of biocontrol agents available. By modelling within a decision-making framework we derived rules of thumb that will enable biocontrol workers to choose between management options, depending on the current state of the system. 3. When there are few well-established sites, making a few large releases is the optimal strategy. For other states of the system, the optimal strategy ranges from a few large releases, through a mixed strategy (a variety of release sizes), to many small releases, as the probability of establishment of smaller inocula increases. 4. Given that the probability of establishment is rarely a known entity, we also strongly recommend a mixed strategy in the early stages of a release programme, to accelerate learning and improve the chances of finding the optimal approach.

Percutaneous absorption of sunscreen agents from liquid paraffin: Self-association of octyl salicylate and effects on skin flux

This study provides an investigation of the availability of octyl salicylate (OS), a common sunscreen agent, from liquid paraffin and the effect of OS on skin permeability. A model membrane system to isolate the vehicle effect from membrane permeability has been developed. Partitioning of OS between liquid paraffin and aqueous receptor phases was conducted. Partition coefficients increased with increase in OS concentration. A range of OS concentrations in liquid paraffin was diffused across human epidermis and synthetic membranes into 4% bovine serum albumin in phosphate-buffered saline and 50% ethanol. Absorption profiles of OS obtained from silicone and low-density polyethylene (LDPE) membranes were similar to each other but higher than for the high-density polyethylene [HDPE (3 times)] membrane and human epidermis (15 times). The steady state fluxes and apparent permeability coefficients (K-p') obtained from the diffusion studies showed the same trends with all membranes, except for the HDPE membrane which showed greater increase in flux and K-p' at concentrations above 30%. IR spectra showed that several bands of OS were shifted with concentrations, and the molecular models further suggested that the main contribution to the self-association is from non-1,4 van der Waals interactions.