Design and therapeutic application of matrix metalloproteinase inhibitors.

The emerging role of cell-free DNA as a molecular marker for cancer management.

Precision medicine in the clinical management of cancer may be achieved through the diagnostic platform called "liquid biopsy". This method utilizes the detection of biomarkers in blood for prognostic and predictive purposes. One of the latest blood born markers under investigation in the field of liquid biopsy in cancer patients is circulating tumor DNA (ctDNA). ctDNA is released by tumor cells through different mechanisms and can therefore provide information about the genomic make-up of the tumor currently present in the patient. Through longitudinal ctDNA-based liquid biopsies, tumor dynamics may be monitored to predict and assess drug response and/or resistance. However, because ctDNA is highly fragmented and because its concentration can be extremely low in a high background of normal circulating DNA, screening for clinical relevant mutations is challenging. Although significant progress has been made in advancing the detection and analysis of ctDNA in the last few years, the current challenges include standardization and increasing current techniques to single molecule sensitivity in combination with perfect specificity. This review focuses on the potential role of ctDNA in the clinical management of cancer patients, the current technologies that are being employed, and the hurdles that still need to be taken to achieve ctDNA-based liquid biopsy towards precision medicine.

Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management.

Circulating Tumor DNA as Biomarkers for Cancer Detection.

Through various pathways of cell death, degradation, and regulated extrusion, partial or complete genomes of various origins (e.g., host cells, fetal cells, and infiltrating viruses and microbes) are continuously shed into human body fluids in the form of segmented cell-free DNA (cfDNA) molecules. While the genetic complexity of total cfDNA is vast, the development of progressively efficient extraction, high-throughput sequencing, characterization via bioinformatics procedures, and detection have resulted in increasingly accurate partitioning and profiling of cfDNA subtypes. Not surprisingly, cfDNA analysis is emerging as a powerful clinical tool in many branches of medicine. In addition, the low invasiveness of longitudinal cfDNA sampling provides unprecedented access to study temporal genomic changes in a variety of contexts. However, the genetic diversity of cfDNA is also a great source of ambiguity and poses significant experimental and analytical challenges. For example, the cfDNA population in the bloodstream is heterogeneous and also fluctuates dynamically, differs between individuals, and exhibits numerous overlapping features despite often originating from different sources and processes. Therefore, a deeper understanding of the determining variables that impact the properties of cfDNA is crucial, however, thus far, is largely lacking. In this work we review recent and historical research on active vs. passive release mechanisms and estimate the significance and extent of their contribution to the composition of cfDNA.

Putative Origins of Cell-Free DNA in Humans: A Review of Active and Passive Nucleic Acid Release Mechanisms.

Paul Brown speaks to Gemma Westcott, Commissioning Editor: Paul Brown has served as the Head of Roche Molecular Diagnostics at Roche Diagnostics Corporation since February 2010 having previously held a variety of positions within Roche Pharma. After completing his doctorate in organic chemistry he was awarded a post-doctoral fellowship at the California Institute of Technology in Pasadena, CA, USA, but soon returned to his native UK to join Roche Pharma Research. Paul's first post within Roche was as group leader, doing drug discovery and making new small molecule drugs, but later moved into the business part of the company. Since then, he has enjoyed roles such as lifecycle leader for brands such as Tamiflu(®) and Xenical, vice president of sales and marketing of the pharmaceutical division and most recently general manager of Roche Pharma, Sweden.

The Cobas® EGFR Mutation Test v2 assay.

The invention provides hydroxamic acid derivatives of the general formula (I) wherein R1 represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R2 represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring which is attached via the N atom and which, when it is monocyclic, optionally contains NR4, O, S, SO or SO2 as a ring memher and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino,carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R3 represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO2 as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group;m stands for 1 or 2 and n stands for 1-4, and pharmaceutically acceptable salts thereof, which are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured either by hydroxamidating a corresponding novel carboxylic acid or by deprotecting a corresponding novel benzyloxycarbamoyl compound.

Hydroxamic Acid Derivatives with Tricyclic Substitution

The invention provides hydroxylamine derivatives of formula (I) wherein A, R?1, R2 and R3? have the significance given in the description, which are matrix metalloproteinase inhibitors and which also prevent TNF release. They are therefore useful for the control or prevention of degenerative joints diseases such as rheumatoid arthritis and osteoarthritis or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured according to generally known methods.

Hydroxylamine derivatives and their use as metalloproteinase inhibiting agents

http://link.springer.com/content/pdf/10.1007/978-94-015-9028-0_7.pdf

Targets for Drug Design

Preparation of optically active 1-A3-cyclopentyl-2(R)-A1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5- dioxo-1-imidazolidinyl)ethylUpropionylpiperidine of formula (I) comprises (a) reaction of a cyclopentenyl-alkoxycarbonyl-succinic acid ester of formula (II) with 3-bromomethyl-1,5,5-trimethylhydantoin in the presence of base to give a tricarboxylic acid derivative of formula (III); (b) hydrogenolysis of (III) in the presence of metal catalyst and decarboxylation in the presence of base, to give the succininc acid compound of formula (IV), and purification of (IV) in the presence of a further, salt-forming, base to give (IV) in the form of its salt; (c) reaction of (IV) with piperidine, under activation of the carboxylic acid, to give the amide of formula (V) (where (V) is either (Va) with R1 = tert. butyl or (Vb) with (R1 not tert. butyl); and either (d) reaction of (Va) with a benzylhydroxylamine hydrochloride (A), where (A) is activated with alkylmagnesium halide, to give 1-A2(R)-A1(R)-benzyloxycarbamoyl-2-(3,4,4-trimethyl-2,5-dioxo-1-imidaz olidinyl)ethylU-3-cyclopentyl-propionylUpiperidine (VII), and hydrogenolysis of (VII) to give (I); or (e) removing the tert. butyl ester group of (Va) using mineral acid and carboxylic acid and/or its ester, and optionally removing the alkyl ester R1 group of (Vb) using alkali or alkaline earth hydroxide, to give 1-A2(R)-A1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)et hylU-3-cyclopentyl-propionylUpiperidine (VI); and either converting (VI) to (VII) and then to (I) as in (d); or reacting (VI) with trimethylsilyl-hydroxylamine or tetrahydropyranyl-hydroxylamine, and removing the trimethylsilyl or tetrahydropyranyl group by standard methods, to give (I). R1 = methyl, ethyl, propyl, butyl, pentyl, hexyl or tert.-butyl; R2 = a group that can be released by hydrogenolysis. (II)-(VII) are new. Also new are intermediates for (II), of formula (XII). X = H or SO2R3; R3 = CF3 or phenyl (optionally substituted by NO2 or halo).

Process for the preparation of chiral succinic acid derivatives

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