Showing papers by "John M. Pezzuto published in 2012"
TL;DR: In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity and LPS-induced nitric oxide production and provided greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects.
Abstract: Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects.
109 citations
TL;DR: It is clear that flavonoids or flavonoid derivatives offer value for the chemoprevention of cancer, and greater emphasis has been placed on the study of methoxylated flavonoidal derivatives, which may demonstrate more favorable pharmacokinetic properties.
Abstract: Flavonoids are widely distributed in nature and a prevalent component of the human diet. Numerous biological activities have been reported. Some clinical trials or meta-analyses have suggested positive associations between flavonoid intake and human health, whereas others have not supported such a relationship. We currently highlight some responses that may be relevant to cancer chemoprevention, including antioxidation, anti-inflammation, and effects on NK cells. In addition, the prooxidant capacity of flavonoids may be relevant for the treatment of cancer. As is the case with other phytochemical constituents found in the diet, many questions over-shadow the results obtained with in vitro studies that do not take into account the ramifications of poor bioavailability, rapid and extensive metabolism, and physiologically relevant concentrations. To overcome some of these difficulties, greater emphasis has been placed on the study of methoxylated flavonoids, which may demonstrate more favorable pharmacokinetic properties. In terms of drug development, newer approaches such as nanotechnology could be useful. It is clear that flavonoids or flavonoid derivatives offer value for the chemoprevention of cancer. Many avenues of development are available and necessary for exploiting the impact on human health.
65 citations
TL;DR: Replacement of the stilbene ethylenic bridge of resveratrol with a 1,2,4-thiadiazole heterocycle and modification of the substituents on the two aromatic rings afforded potential chemopreventive agents with enhanced potencies and selectivities when evaluated as inhibitors of aromatase and NF-κB and inducers of quinone reductase 1 (QR1).
65 citations
TL;DR: Whether plants with ethnomedical uses from Vietnam and Laos have a higher hit rate in bioassay testing than plants collected from a national park in Vietnam with the goal of maximizing taxonomic diversity (“random” collection) is analyzed.
Abstract: Post print version of article may differ from published version. The definitive version is available through Pharmaceutical Biology © 2012 Informa Healthcare. DOI: 10.3109/13880209.2011.634424
47 citations
TL;DR: Bioassay-guided fractionation of the hexane extract from the flowers of Vernonia cinerea led to the isolation of a new sesquiterpene lactone, 8 α-hydroxyhirsutinolide, and a new naturally occurring derivative, 8α-hydroxyl-1-O-methylhirsUTinolides, along with seven known compounds.
40 citations
TL;DR: Ethnobotanical survey has demonstrated the richness of plant-based traditional medicine of Lao PDR, taxonomically and therapeutically, and yielded a series of new bioactive compounds against the diseases of cancer and malaria.
Abstract: Post print version of article may differ from published version. The definitive version is available through Informa Healthcare at DOI: 10.3109/13880209.2011.619700
38 citations
TL;DR: Preliminary mechanistic studies revealed that abyssinone II hyperpolarizes the bacterial membrane potential and inhibits the biosynthesis of key cellular macromolecules (DNA, RNA, and protein).
Abstract: The growing prevalence of antibiotic-resistant pathogens continues to drive the need for antibiotics with novel modes of action. Of particular concern are infections caused by multidrug- resistant Mycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), penicillin-resistant Streptococcus pneumoniae, fluoroquinolone-resistant Pseudomonas aeruginosa (FQRP), and β-lactam-resistant Gram-negative organisms, since many of these pathogens are intransigent to multiple classes of drugs.[1–3] Among discovery strategies, the empirical screening of chemical entities that are structurally distinct from clinically established agents represents an effective approach to developing novel antibiotics.
33 citations
TL;DR: The moderate and non-selective aromatase inhibitory activity of resveratrol was improved by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines and enhanced over 6000-fold by using a 1,3-thiazole as the central ring.
32 citations
TL;DR: Optizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to a highly potent and selective QR1 inducer 9o with a CD value of 0.087 μM.
26 citations
TL;DR: Synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFκB inhibitors with antiinflammatory and cancer preventive potential.
Abstract: Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFκB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NFκB with IC50 values of 38.1 ± 1.8 and 25.4 ± 2.1 μM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFκB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2–7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC50 = 4.4 ± 0.5 and 4.8 ± 0.4 μM, respectively); as well as NFκB inhibition (IC50 = 6.9 ± 0.8 and 8.5 ± 2.0 μM, respectively). In addition, the 6′-MeO-naphthalen-2′-yl indole derivative 10at displayed excellent inhibitory activity against NFκB with an IC50 value of 0.6 ± 0.2 μM.
23 citations
TL;DR: The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.
Abstract: Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.
TL;DR: Thienodolin inhibited nitric oxide production in LPS-stimulated RAW 264.7 cells and blocked the degradation of IκBα resulting in inhibition of NF-κB p65 nuclear translocation, and inhibited the phosphorylation of signal transducers and activators of transcription 1 (STAT1) at Tyr701.
Abstract: The measurement of nitric oxide in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells is used as a model for evaluating the anti-inflammatory or chemopreventive potential of substances. Thienodolin, isolated from a Streptomyces sp. derived from Chilean marine sediment, inhibited nitric oxide production in LPS-stimulated RAW 264.7 cells (IC50 = 17.2 +/- 1.2 microM). At both the mRNA and protein levels, inducible nitric oxide synthase (iNOS) was suppressed in a dose-dependent manner. Mitogen-activated protein kinases (MAPKs), one major upstream signaling pathway involved in the transcription of iNOS, were not affected by treatment of thienodolin. However, the compound blocked the degradation of IkappaBa resulting in inhibition of NF-kappaB p65 nuclear translocation, and inhibited the phosphorylation of signal transducers and activators of transcription 1 (STAT1) at Tyr701. This study supports further exploration of thienodolin as a potential therapeutic agent with a unique mechanistic activity.
TL;DR: Investigation into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFκB signaling pathway, aromatase inhibition, induction of quinone reductase 1 expression, and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules.
Abstract: Several lactone- and lactam-based neoflavonoids and tetrahydroquinolones were synthesized and evaluated for cancer chemopreventive studies using cell and molecular target-based in vitro bioassays, namely NFκB, aromatase, and quinone reductase 1. These analogs blocked TNF-α-induced NFκB activation in a dose-dependent manner with IC₅₀ values in the range of 0.11-3.2 μM. In addition, compound 8 inhibited aromatase activity with an IC₅₀ value of 12.12 μM, and compound 10 affected quinone reductase 1 induction (IR, 3.6; CD, 19.57 μM). Neoflavonoids 8 and 10 exhibiting good results can further be optimized for improved therapeutic profiles. However, investigations into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFκB signaling pathway, aromatase inhibition, induction of quinone reductase 1 expression, and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules.
TL;DR: Taken together, AM6-36 might serve as an effective anticancer agent by inducing G2/M cell cycle arrest and apoptosis through the activation of MAPKs and inhibition of c-Myc.
Abstract: Recently, we reported that 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (AM6-36), sharing structural similarity with naturally occurring isoquinolines, induced activities mediated by retinoid X receptor (RXR) response element accompanied by antiproliferative effects on breast cancer cells To further characterize the biologic potential of AM6-36, we currently report studies conducted with HL-60 human leukemia cells AM6-36 significantly inhibited cellular proliferation in a dose- and time-dependent manner with an IC50 value of 86 nM When evaluated at low test concentrations (≤025 μM), AM6-36 induced arrest in the G2/M phase of the cell cycle At higher concentrations (1 and 2 μM), the response shifted to apoptosis, which was consistent with the effect of AM6-36 on other apoptotic signatures including an increase of apoptotic annexin V+ 7-AAD– cells, loss of mitochondrial membrane potential, induction of poly(ADP-ribose) polymerase cleavage, and activation of several cas
TL;DR: A historical perspective of the growth and development of Pharmaceutical Biology is presented.
Abstract: A historical perspective of the growth and development of Pharmaceutical Biology.