Oxazole and thiazole analogs of sulindac for cancer prevention

Aim: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs.Conclusion: In general, replacement of the amide function of SSA analogs had a negative impact on the cell lines tested. A small number of hits incorporating rigid oxazole or thiazole groups in the sulindac scaffold in place of the amide linkage show comparable activity to our lead agent SSA.</p

Diverse amide analogs of sulindac for cancer treatment and prevention

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development

Screening and development of new inhibitors of FtsZ from <i>M. Tuberculosis</i>

A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics

A randomised clinical trial of a comprehensive exercise program for chronic whiplash: trial protocol

Background: Whiplash is the most common injury following a motor vehicle accident. Approximately 60% of people suffer persistent pain and disability six months post injury. Two forms of exercise; specific motor relearning exercises and graded activity, have been found to be effective treatments for this condition. Although the effect sizes for these exercise programs, individually, are modest, pilot data suggest much larger effects on pain and disability are achieved when these two treatments are combined. The aim of this study is to investigate the effectiveness and cost-effectiveness of this comprehensive exercise approach for chronic whiplash

Dry needling and exercise for chronic whiplash - a randomised controlled trial

Chronic whiplash is a common and costly problem. Sensory hypersensitivity is a feature of chronic whiplash that is associated with poor responsiveness to physical treatments such as exercise. Modalities such as dry-needling have shown some capacity to modulate sensory hypersensitivity, suggesting that when combined with advice and exercise, such an approach may be more effective in the management of chronic whiplash. The primary aim of this project is to investigate the effectiveness of dry-needling, advice and exercise for chronic whiplash

Clinical and Experimental Applications of NIR-LED Photobiomodulation

This review presents current research on the use of far-red to near-infrared (NIR) light treatment in various in vitro and in vivo models. Low-intensity light therapy, commonly referred to as “photobiomodulation,” uses light in the far-red to near-infrared region of the spectrum (630–1000 nm) and modulates numerous cellular functions. Positive effects of NIR–light-emitting diode (LED) light treatment include acceleration of wound healing, improved recovery from ischemic injury of the heart, and attenuated degeneration of injured optic nerves by improving mitochondrial energy metabolism and production. Various in vitro and in vivo models of mitochondrial dysfunction were treated with a variety of wavelengths of NIR-LED light. These studies were performed to determine the effect of NIR-LED light treatment on physiologic and pathologic processes. NIRLED light treatment stimulates the photoacceptor cytochrome c oxidase, resulting in increased energy metabolism and production. NIR-LED light treatment accelerates wound healing in ischemic rat and murine diabetic wound healing models, attenuates the retinotoxic effects of methanol-derived formic acid in rat models, and attenuates the developmental toxicity of dioxin in chicken embryos. Furthermore, NIR-LED light treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. The experimental results demonstrate that NIR-LED light treatment stimulates mitochondrial oxidative metabolism in vitro, and accelerates cell and tissue repair in vivo. NIR-LED light represents a novel, noninvasive, therapeutic intervention for the treatment of numerous diseases linked to mitochondrial dysfunction

Discovery of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug

Repositioning: the fast track to new anti-malarial medicines?

Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages. Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at muM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.This work was supported by the Medicines Malaria Venture, St Jude Children's Research Hospital, GlaxoSmithKline Plc and Pfizer Inc