ABSTRACT
Kinetic target-guided synthesis (KTGS) is an original discovery strategy allowing a target to catalyze the irreversible synthesis of its own ligands from a pool of reagents. Although pioneered almost two decades ago, it only recently proved its usefulness in medicinal chemistry, as exemplified by the increasing number of protein targets used, the wider range of target and pocket types, and the diversity of therapeutic areas explored. In recent years, two new leads for in vivo studies were released. Amidations and multicomponent reactions expanded the armamentarium of reactions beyond triazole formation and two new examples of in cellulo KTGS were also disclosed. Herein, we analyze the origins and the chemical space of both KTGS ligands and warhead-bearing reagents. We review the KTGS timeline focusing on recent cases in order to give medicinal chemists the full scope of this strategy which has great potential for hit discovery and hit or lead optimization.
Subject(s)
Chemistry, Pharmaceutical/trends , Drug Delivery Systems/trends , Drug Discovery/trends , Protease Inhibitors/chemistry , Protein Synthesis Inhibitors/chemistry , Animals , Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Drug Discovery/methods , Humans , Kinetics , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Protein Synthesis Inhibitors/administration & dosage , Protein Synthesis Inhibitors/pharmacokineticsABSTRACT
Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.
Subject(s)
Antineoplastic Agents/therapeutic use , DNA Methylation , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Chromatin/genetics , Chromatin/metabolism , Clinical Trials as Topic , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Enzyme Inhibitors/pharmacology , Epigenesis, Genetic/drug effects , Gene Silencing , Histone Methyltransferases , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/metabolism , Histones/metabolism , Humans , Neoplasms/enzymology , Neoplasms/geneticsABSTRACT
Introducción: Los tumores quísticos representan el 1% de todos los tumores primarios del páncreas y sólo el 15% de las lesiones quísticas. Los cistoadenomas serosos (SCA) son lesiones casi siempre benignas con un tamaño promedio de 4 cm, sin embargo en raros casos existen lesiones de mayor tamaño que ocasionalmente producen síntomas relacionados al efecto de masa y compresión de estructuras vecinas, se presenta el caso de una paciente con imagen tomográfico de lesión en cola de páncreas de 10 cm. de diámetro que se le realizó pancreatectomía caudal y esplenectomía video laparoscópica. Se confirmó el diagnóstico por anatomía patológica. Se realiza una revisión bibliográfica de la enfermedad, opciones diagnósticas y terapeúticas.
Introduction: Cystic tumors represent 1% of all primary Pancreatic Tumors and only 15% of cystic lesions. The serous cystadenomas (SCA) are almost always benign lesions with an average size of 4 cm, however in rare cases there are larger lesions which occasionally produce symptoms related to the mass effect and compression of surrounding structures, arises the tomographic image patient case of injury in tail of pancreas of 10 cm. in diameter that caudal pancreatectomy and video-assisted laparoscopic Splenectomy were performed. The diagnosis was confirmed by pathology. He is a literature review of disease, diagnostic options, and therapeutic.
Subject(s)
Female , Humans , Middle Aged , Cystadenoma, Serous , Cystadenoma, Serous/diagnosis , Pancreatic Neoplasms/surgeryABSTRACT
INTRODUCTION: Quinazoline is one of the most studied moieties in medicinal chemistry due to the wide range of biological properties such as the anticancer, antibacterial, anti-inflammatory, antimalarial and antihypertensive activities. During the past decades, several patents and articles have been published in international peer-reviewed literature regarding the discovery and development of original and promising quinazoline derivatives for cancer treatment. Although quinazolines are well known to inhibit EGFR, there is also a large panel of other therapeutic protein targets. AREAS COVERED: This review summarized the new patents and articles published about quinazoline derivatives as anticancer drugs since 2011. EXPERT OPINION: Since 2011, a lot of quinazoline compounds have shown EGFR inhibition. Unlike the first-generation EGFR inhibitors, they inhibit both wild-type and mutated EGFR. In recent years, a number of studies on quinazoline synthesis have been reported and used by several medicinal chemistry groups for better and easier development of new derivatives. Therefore, several patents have been approved for the use of quinazoline compounds as inhibitors of other kinases, histone deacetylase, Nox and some metabolic pathways. Because of the large number of proteins targeted, some high structural diversity is observed in patented quinazoline compounds. Due to the vast applications of quinazoline derivatives, development of novel quinazoline compounds as anticancer drugs remains a promising field.
