- Reaction vials pre-filled with reagents and stir bar.
- Multiple format and vials available
- Microwave or conventional heating
- Pre-designed or custom arrays available
- Reagents are packaged under inert atmosphere
ACS Expo 2016 August 21st-23rd
Please come visit HepatoChem Booth #338 at the 252nd American Chemical Society National Meeting & Exhibition to discover our new catalog of chemistry kits.
Late stage functionalization kits
Pre-Filled Reaction Vials
In recent years, amide coupling has become the most frequently used reaction in medicinal chemistry1. Found as the backbone of proteins, the amide bond is nominal formed by the condensation of a carboxylic acid and an amine. Due to a nearly unlimited set of readily available carboxylic acid and amine derivatives, amide coupling strategies can be an efficient approach for medicinal chemists to generate novel compounds. As a result of this utility, a nearly unlimited set of reagents and protocols have been development to afford this simple transformation of amide bond formation2,3.
Amide Bond Formation
The most common method for formation of an amide bond is the condensation of a carboxylic acid and an amine. Generally, the carboxylic acid needs to be activated in order to react with the amine while remaining reactive functional groups need to be protected. This process occurs in two steps in either one pot with direct reaction of the activated carboxylic acid or in two steps with isolation of an activated “trapped” carboxylic acid with reaction with an amine.
Two step peptide bond formation
The carboxylate reacts with the coupling reagent yielding a reactive intermediate which can often be isolated or used immediately with an amine to form an amide bond. A wide variety of reagents have commonly been used to generate the activated carboxylic acid such as an acid halide (chloride, fluoride), azides, anhydrides, or carbodiimides. Additionally, active esters such as pentafluorophenyl or hydroxysuccinimido esters can be prepared as reactive intermediates. Reactive intermediates derived from generation of acyl chlorides or azides are highly efficient for amide coupling; however, their harsh formation and high reactivity often limits use with complex substrates or amino acids. A broadly applicable method for the formation of amide bonds use carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) for activation. Additives are often required to improve the efficiency of the reactions especially for solid-phase synthesis.
To avoid side reactions involving the substituents on the two coupling components, it is often necessary to carefully select the appropriate peptide-coupling reaction condition. One common problem with the use of carbodiimides is the racemization of amino acids. To remedy this, two classes of coupling reagents: Phosphonium and aminium reagents represent significant improvements over carbodiimide methods.
Common Aminium reagents
Common Phosphonium reagents
Aminium salts are very efficient peptide coupling reagents with quick reaction times and minimal racemization. With the addition of an additive such as HOBt, racemization can be completely eliminated. Aminium reagents are used in equal molarity to the carboxylic acid to prevent excess reagent reacting with the free amine of the peptide preventing coupling. Phosphonium salts react with carboxylate requiring usually 2 equivalent of base. (such as DIEA). One key advantage for the use of phosphonium salts over iminium reagents is that phosphonium does not reactive with the free amino group of the amine component. This allows couplings to occur in equimolar relation between the acid and amine, highly advantageous in situations such as the intramolecular cyclization of linear peptides or examples where excess of valuable amine component is discouraged.
Choosing the correct reaction for your needs:
While amide bond formation is a straightforward reaction, the choice of suitable reagents for an individual coupling of a complex carboxylic acid and amine may be a difficult decision. A variety of factors can be involved in finding the optimal peptide coupling reaction. Unanticipated side reactions or rearrangements, low conversions, solubility issues, or incompatibility with additional synthetic steps can all hinder what would appear to be a straightforward amide coupling reaction. As such, it is often necessary to draw from the large number of available reagents and protocols to find the optimal reaction condition. Screening a selection of reagents can often find a suitable reaction for any amide coupling.
1. Brown, Dean G., Bostrom, Jonas, “Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?” J. Med. Chem., 2015, ASAP.
2. El-Faham, Ayman; Albericio, Fernando, “Peptide Coupling Reagents, More than a Letter Soup” Chem. Rev., 2011, 111, 6557.
2. Pattabiraman, Vijaya R., Bode, Jeffrey W. “Rethinking Amide Bond Synthesis” Nature, 2011, 480, 471.
Methyl groups are very common in drug molecules. As reported by Heike Schonherr and Tim Cernak1, more than half of the top-selling drugs contains a CH3. A simple substitution of a C-H with a methyl can increase the potency of a compound by more than 100-fold.
The effect of C-H methylation primarily affects the conformation of the original molecule. Based on this reported statistical analysis2 the effect of methyl can be equally positive or negative. However a positive effect could be decisive in a drug discovery program.
Effect of ortho substitution3,4.
Effect of ring substitution5
Effect on rotatable bond6
Even if the methyl can be seen as a potential hot spot for metabolism. The addition of the methyl next to a metabolism position can improve metabolic stability.7
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Palladium based catalysis is the most used tool to perform the formation of C-C, C-O and C-N. There are many sources of palladium such as PdOAc2, PdCl2 or Pd2dba3. However the related methods do not always allow sufficient conversion.
Palladium precatalysts is an efficient solution to generate in-situ the LnPd(0) needed for the reaction. These precatalysts are generally air and moisture stable.
The first palladacycle precatalyst has been reported by Herman and Beller in 19951. Since then Buchwald laboratories has developed several types of palladium.
The first generation of Buchwald palladium precatalysts are phenethylamine derivatives. In presence of a base the LPd(0) can be generated in-situ.
The second generation of Buchwald palladium precatalysts are 2-aminobiphenyl derivatives. These precatalysts can be activated at room temperature.
The third generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-aminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.
The fourth generation of Buchwald palladium precatalysts are methylsulfonate salt of 2-methylaminobiphenyl derivatives. These precatalysts are compatible with bulky ligands and show longer stability in solution.
1 Herman,W.A.; Beller,M. Angew. Chem. Int. Ed., 1995, 34, 1844-1848.
In medicinal chemistry, fluorine substitution of alkyl or aryl hydrogen is an increasingly popular strategy to optimize lead compounds. Fluorine offers unique properties. It is almost as small as a hydrogen but very electronegative. The C-F bond is highly polarized.
The polarity of the C-F bond influences the conformation of aliphatic systems.
It is generally accepted that fluorine can interact with hydroxyl, amine and amide functions through hydrogen bond interaction and induce specific conformation.
The electron-withdrawing properties of fluorine can reduce pKa of amines and make them less basic. The similar effect is observed on carboxylic acids and make them more acidic. The change in pKa will influence conformation, potency, permeability, and pharmacokinetic properties.
CH3CO2H 4.8 CH2FCO2H 2.6
(CH3)2CHOH 17.1 (CF3)2CHOH 9.3
CH3CH2NH2 10.7 CF3CH2NH2 5.7
Because of the strength C-F bond, fluorine substitution of a hydrogen is a common way to improve stability. It can be done in both aliphatic and aromatic systems. Fluorine will also increase metabolic stability of electron-rich aromatic ring.
Eric P. Gillis, Kyle J. Eastman, Matthew D. Hill, David J. Donnelly, and Nicholas A. Meanwell, Applications of Fluorine in Medicinal Chemistry, J. Med. Chem., 2015
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Dr Ryan Buzdygon will be presenting “Late-stage functionalization platform for lead optimization and diversification: Generation of high value compounds directly for biological testing” at ACS Boston. Stop by on Wednesday August 19th during the General Posters Session for the Division of Medicinal Chemistry from 7:00 PM – 9:00 PM in the Ballroom at the Boston Convention & Exhibition Center to hear about our late stage diversification platform.
Lenexa, KS, August 19th, 2014 — XenoTech announces an exclusive partnership with HepatoChem to offer fast and cost-effective metabolite production from bioactive small molecules. Based on an innovative and proprietary chemistry platform, the technology enables convenient and timely assessment of critical metabolite and toxicity issues. According to XenoTech’s Vice President of Commercial Operations, Christian Darabant, “the value of rapid metabolite synthesis for assessing clinical risk can be measured directly by comparison with the approximate $2 million per day cost impact of each day of delay in a drug’s development.”
Metabolite synthesis is critical in the drug development process as it allows researchers to accurately evaluate metabolites in safety toxicity as well as promoting identification and isolation of pharmacologically active metabolites. According to Marc Bazin, HepatoChem’s CEO, “current technologies are designed to identify metabolites but are unable to produce testable quantities of metabolites. Consequently, metabolite studies are delayed (a calculated risk) in the drug delivery process; having access to milligram quantities of drug metabolite permits resolution of many of the fundamental questions surrounding small molecule metabolism. The biomimetic technology speeds up metabolite studies to allow rapid improvement of the metabolic properties of drug candidates.” XenoTech’s Executive Vice President & COO, Jason Neat, further explains, “Combining XenoTech’s ability to effectively elucidate metabolite formation through biological processes with the ability to efficiently produce milligram quantities of metabolites of interest for further evaluation is a benefit we must bring to our clients. By pairing XenoTech’s in vitro DMPK expertise with HepatoChem’s innovative platform, we are able to offer a tremendous and comprehensive solution to our customers for risk mitigation.”
The innovative technology uses biomimetic catalysts to mimic oxidative metabolism which synthesizes metabolites from the parent drug. The catalytic conditions are as selective as enzyme specificity achieved with microsomes or hepatocytes yet have the advantage of enabling metabolite production in milligram quantities. This unique system offers a highly competitive, higher-yield, cost-effective alternative to biological metabolite synthesis, facilitating knowledge early in the development process for informed program decision-making. Researchers around the world will benefit from this synergistic pairing of XenoTech’s distinguished expertise and holistic approach to drug metabolism research with HepatoChem’s unique, effective and efficient biomimetic oxidation platform. Biomimetic metabolite synthesis is now offered as both a service, with the work performed by the expert scientists at XenoTech and HepatoChem or for in-house work as a product, allowing customers the freedom to synthesize metabolites in their own laboratories via the BMO™ Kit.
XenoTech, LLC is a global Contract Research Organization with unparalleled experience and expertise in evaluating drug candidates, nutraceuticals, cosmetics, food additives and other compounds widely known as xenobiotics, substrates, inhibitors and inducers of cytochrome P450, UGT and other drug metabolizing enzymes and drug transporters. The company offers a variety of in vitro and in vivo safety assessment studies for drug candidate evaluation, as well as an extensive selection of products for drug metabolism research. XenoTech’s product selection includes a wide-range of high quality standard reagents, from subcellular fractions and hepatocytes to recombinant enzymes, substrates and metabolites. The company can also prepare and deliver custom-designed products and services in respnose to client requests. For additional information, please refer to the company’s website at www.xenotechllc.com or call (913) 438-7450.
HepatoChem, Inc. of Beverly, Massachusetts was founded in 2008, is a life science company that has developed its technology platform through a partnership with Princeton University. HepatoChem focuses on early stage development with a game-changing, proprietary chemistry platform that enables fast and cost-effective metabolite production from bioactive small molecules. The HepatoChem technology enables assessment of critical metabolite and toxicity issues early in the R&D continuum, reducing the risk of failure in clinical development of drug candidates. For more information, visit www.hepatochem.com