Design and discovery of novel quinazolinedione-based redox modulators as therapies for pancreatic cancer.

BACKGROUND: Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling. METHODS: Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots. RESULTS: Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of ~1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity. CONCLUSION: In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further preclinical studies. GENERAL SIGNIFICANCE: Since 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) exerts Akt-dependent ROS-mediated cell death, it might provide potential therapeutic options for chemoresistant and Akt-overexpressing cancers.

Design and synthesis of novel dihydroquinoline-3-carboxylic acids as HIV-1 integrase inhibitors.

Previously, we discovered linomide analogues as novel HIV-1 integrase (IN) inhibitors. Here, to make possible structure-activity relationships, we report on the design and synthesis of a series of substituted dihydroquinoline-3-carboxylic acids. The crystal structure of the representative compound 2c has also been solved. Among the eight new analogues, 2e showed a potency in inhibiting IN strand transfer catalytic activity similar to the reference diketo acid inhibitor L-731,988 (IC(50)=0.9 microM vs. 0.54 microM, for 2e and L-731,988, respectively). Furthermore, none of the compounds showed significant cytotoxicity in two tested cancer cell lines. These compounds represent an interesting prototype of IN inhibitors, potentially involved in a metal chelating mechanism, and further optimization is warranted.

Discovery of novel non-cytotoxic salicylhydrazide containing HIV-1 integrase inhibitors.

The previously discovered salicylhydrazide class of compounds displayed potent HIV-1 integrase (IN) inhibitory activity. The development of this class of compounds as antiretroviral agents was halted due to cytotoxicity in the nanomolar to sub-micromolar range. We identified a novel class of non-cytotoxic hydrazide IN inhibitors utilizing the minimally required salicylhydrazide substructure as a template in a small-molecule database search. The novel hydrazides displayed low micromolar IN inhibitory activity and are several hundred-fold less cytotoxic than previously disclosed salicylhydrazide IN inhibitors.

Restoration of Traditional Children's Play in Iranian Nomadic Societies (Case Study of Kohgilouyeh and Boyer Ahmad).

This article aims to provide an insight into play as an important aspect of children's lives in an under-studied area of Iran. Our observations focus on the province of Kohgilouyeh and Boyer Ahmad with its ancient nomadic cultures. Through first-hand knowledge and lived experiences, supplemented by available literature, we seek to look at children's games in the frame of culture change, exploring their relationship with children's health and wellbeing. Play, as in every region in the world, conveys and reflects the dominant culture and teaches the values of the society in which the children live in the here and now and in which they will have to function as adults. Yet, types of play are not static. They develop alongside social, political and economic changes and embrace new forms emerging from modern lifestyles. The latter sometimes come into conflict with and challenge the local culture and traditional types of play, which are based on the lives and histories of the indigenous peoples and local communities. A sample of traditional tribal forms of play is analyzed for their health, entertainment and fun aspects. Such play allows children to prepare for life's realities, in particular for a life of cooperation. By contrast, whilst also providing children with tools and skills for the needs of modern life, new types of play focus more on competition and individualism. This divergence expressed in different types of play widens the generation gap and contributes to alienation. The shift from a collective to individualistic lifestyle thus has an unsettling impact on the community and impacts on the emotional and physical wellbeing of children. We will describe types of play and their role in the holistic development of nomadic children, as well as the impact of modernization and social change, including sedentarization. The article will highlight some consequences of the demise of indigenous play, through observation and analytical comparison of children's play in three generations. Based on the insights gained, the authors offer recommendations on how to restore traditional play and games through redesigning them to be capable of adaptation to changes in lifestyles.

Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity.

BACKGROUND: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. METHODOLOGY/PRINCIPAL FINDINGS: A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. CONCLUSIONS/SIGNIFICANCE: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling.

Discovery of novel anticancer compounds based on a quinoxalinehydrazine pharmacophore.

Quinoxalinehydrazines represent a novel class of compounds with excellent potency in a panel of cancer cell lines. A prototype compound, SC144, showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. The subsequent structure-activity relationship study resulted in the discovery of SC161 with better potency in cancer cell lines. Further exploring the possible conformational space by a 10 ns molecular dynamics simulation as presented herein, resulted in various pharmacophore orientations. The trajectory analysis indicated that in most of the simulation time, the molecule stays favorably in a compact planarlike orientation. We therefore built a pharmacophore model based on the cluster containing the highest number of frames to represent the most probable orientation. The model was used to screen a subset of our small molecule database containing 350,000 compounds. We selected 35 compounds for the initial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazine and quinoline class displayed cytotoxicity in various cancer cell lines. Five of them, compounds 2, 6, 15, 16, and 19, all bearing an oxadiazolopyrazine scaffold, showed IC(50) values <3 muM in certain tumor cell lines. The most potent compound, 2, showed IC(50) values <2 muM in HCT116 p53(+/+), HCT116 p53(-/-), and HEY cells, and 8 muM in NIH3T3 cells. This study shows that conformational sampling of a lead small molecule followed by representative pharmacophore model development is an efficient approach for the rational design of novel anticancer agents with similar or better potency than the original lead but with different physicochemical properties.