356 research outputs found
Small molecule inducers of reactive oxygen species and inhibitors of mitochondrial activity
No full textRaltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors
No full textAbstract Correction to Erik Serrao, Srinivas Odde, Kavya Ramkumar and Nouri Neamati: Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 2009, 6:25. Since the recent publication of our article (Neamati, Retrovirology 2009, 6:25), we have noticed an error which we would like to correct and we would like to apologise to the readers for this mistake.</p
SMALL MOLECULES INDUCERS OFREACTIVE OXYGEN SPECIES AND INHIBITORS OF MITOCHONDRIAL ACTIVITY
No full textThis invention is in the field of medicinal chemistry. In particular, the invention relates to a new classe of small molecules having a quinazolinedione structure with function as reactive oxygen species (ROS) inducers and inhibitors of mitochondrial activity within cancer cells (e.g. pancreatic cancer cells), and their use as therapeutics for the treatment of cancer (e.g. pancreatic cancer) and other diseases
Viral enzymes containing magnesium: metal binding as a successful strategy in drug design
No full textMetal-activated enzymes are important targets in drug discovery in general and for antivirals in particular. Such proteins contain one or more metal ion cofactors, prevalently located in the active site, which are essential to perform biological functions. Understanding enzyme structure and mechanism at a molecular level is important for the design of specific inhibitors that can be used for pharmacological purposes. Because of their peculiar physicochemical characteristics, magnesium ions participate in many catalytic processes involved in nucleic acid biochemistry, thus playing a pivotal role in the replication of many different viruses. In this context, chelation of the magnesium ions cofactors represents an attractive and validated strategy for the development of novel antiviral agents. In many cases, the starting point of the design of efficient drugs was identified in the β-diketoacid prototypes, which evolved in novel chemotypes bearing various chelating motifs able to bind these divalent metal ions. The application of this strategy has allowed significant results to be achieved in recent years in the development of antiviral agents, culminating in the approval of the first HIV integrase inhibitor in 2007.
This review focuses on the magnesium metal cofactors and on their catalytic and biological properties, as well as on the structural features of the most relevant metal chelating compounds developed as antiviral agents against some of the most important viral targets: human immundeficiency virus integrase, reverse transcriptase RNase H, influenza virus endonuclease, and hepatitis C virus polymerase.</br
Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma
No full textAltering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as NQO1, HMOX1, DDIT3, and HSPA5. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with QD325 were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC
Single amino acid substitution in HIV-1 integrase catalytic core causes a dramatic shift in inhibitor selectivity
No full textHIV-1 integrase (IN) mediates the insertion of viral
cDNA into the cell genome, a vital process for replication. This
step is catalyzed by two separate DNA reaction events, termed
30-processing and strand transfer. Here, we show that six inhibitors
from five structurally different classes of compounds display
a selectivity shift towards preferential strand transfer inhibition
over the 30-processing activity of IN when a single serine is
substituted at position C130. Even though IN utilizes the same
active site for both reactions, this finding suggests a distinct conformational
dissimilarity in the mechanistic details of each IN
catalytic event
Mechanisms underlying the cytotoxicity of a novel quinazolinedione‐based redox modulator, QD 232, in pancreatic cancer cells
No full textPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109817/1/bph12855.pd
Structural Investigation of 3,5-Disubstituted Isoxazoles by 1H-Nuclear Magnetic Resonance
No full textSynthesis of bis-amides and hydrazide-containing derivatives of malonic acid as HIV-1 integrase inhibitors
No full textWith the aim to identify novel and/or unified putative pharmacophore required for activity
we selected and formally combinated the main structural motifs of I and II together to the
hydrazide fragment of compounds III and IV, previously reported as new class of
selective IN inhibitors having antiviral activity. Also, the possibility to generate a potential
metal chelating pharmacophore has been considered. With this in mind, we designed two
sets of symmetrical and unsymmetrical bis-amides and hydrazide derivatives of malonic
acid
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