Synthetic Chemistry
During its 25 years’ history, ChemDiv has developed an arsenal of proprietary approaches towards fast, tractable and, even more importantly, novel chemistries. Examples include cascade addition-cyclization, multi-component reactions, one-pot syntheses, assemblies of macrolide-mimetics, spiro– medium- and large(macro) heterocyclic systems, isosteric replacements of aminoacids, di-/tri-peptides and many other unique protocols.
Several notable advantages offered by our synthetic team include:
CUSTOM SYNTHESIS
Our teams of highly skilled scientists have formidable experience in addressing your synthetic, medicinal, building blocks, medicinal chemistry and compound optimization needs. It is this combination of a robust science, discovery chemistry expertise and transparent business/financial models that allowed us to offer Chemistry Systems on Demand™ approach. Specifically, we provide you with a set of our validated chemistries and respective scaffolds for your assessment followed by synthesis of large or small (target/purpose-focused) custom screening compounds. Alternatively, we are happy to accommodate your chemical development ideas in order to convert them into compound libraries that uniquely suit your project needs.
- Fast turn-around time in assessing project feasibility, cost and timing
- Management of a project by both science and business-focused professionals
- Development of your proprietary chemistries or compound library design based on our proprietary templates
- Estimated 10,000 scaffolds to choose from
- Synthetic, scale-up or medicinal chemistry and target considerations for design
- Computational and modeling assessment of target relevance, drug-/lead-like character
- Implementation of your custom selection criteria and filters
- Flexible compound library format: 20-500 analogs/scaffold, diverse plating and delivery capabilities/logistics
- Proprietary collection of ca. 4,000 building blocks
- Development and transfer of protocols and key intermediates
- Material(s) delivery on a 1 mg to 10 kg scale
- Custom plating, solution or dry film formats
- Purification to your specifications
- High-throughput H-NMR, LC/MS and HPLC-based purification if needed
EXPERTISE
- Heterocyclic chemistry
- Aromatic and unsaturated heterocycles
- Natural products and natural-like systems including optically active screening compounds
- Heterocyclic systems with improved solubility and stability
- Macrolides and their analogues
- Medium- and large ring systems with calculated drug-like properties
- ‘Topologically’ rigid screening compounds including spiro- and bridged heterocycles
- High ‘unsaturation’ (Fsp3) content on demand
- Modern techniques
- Organometallic chemistry: Suzuki, Sonogashira, Heck, Grubbs, Buchwald; large scale Li, Mg, Zn, Cu, Au – mediated reactions, etc.
- Enantioselective assembly including catalysis;
- Medium-/large-ring systems assembly including template-guided multi-component reactions, nucleophilic aromatic substitution, metathesis and others;
- Cascade addition, cycloaddition, multi-component cyclization(s);
- Microwave-assisted synthesis, both liquid and solid phase;
- Green chemistry;
- Liquid crystals;
- High throughput analysis (LCMS, HPLC, multi-nuclear NMR)
- High throughput purification (HPLC, mass-directed HPLC, SPE, UV FPLC)
- Solid support chemistry
- 10-10,000 compound parallel synthesis
- Solid-phase catalysts, scavenger resins
- Gram scale solid phase synthesis
- Optically active materials
- Asymmetric synthesis
- Enantiomers and diastereomers: synthesis, separation and identification
- Analysis and purification (chiral HPLC, optical rotation, LSR)
- Absolute and relative stereochemistry assignment (X-ray)
- Peptidomimetics and unnatural amino acids and derivatives
- Special conditions
- High pressure reactions (up to 200 bar)
- Large scale hydrogenation
- Large scale reactions (up to 30 L)
- Large scale purification
- Scale up
SYNTHETIC PATHWAYS DESIGN
Multiple considerations go into the design of templates, compound libraries and unique molecules. Naturally, ChemDiv takes into consideration and implements every specific consideration of our Clients. Additionally, key guidelines of modern discovery chemistry including both chemical and biological aspects are involved:
- Template/screening compound novelty, and intellectual property status;
- Drug- or lead-likeness, including lipophilicity, biomembrane/blood-brain barrier permeability, Fsp3 character, ligand efficiency vs. lipophilic ligand efficiency and (yes!) water solubility
- Relevance to specific Biological goals, for example targets, target classes, pathways, and cellular processes
- Diversity as compared to the developed commercial chemical space or pertinent to your specific needs
- Synthetic considerations: feasibility, building blocks (commercial and/or project and compound library specific, including your proprietary selection)
- Rapid expansion to launch structure-activity relationship (SAR) studies of representative molecules
At ChemDiv, we are always ready to incorporate your specific needs into every step of the design process.
SYNTHETIC PATHWAYS VALIDATION
Every chemical procedure is as good as its validation. At ChemDiv, we pay specific attention to this crucial step of discovery chemistry. Once the protocol is suggested and adopted, our team of chemists evaluates reagents, conditions, feasibility, scaleability and safety in a multi-parameter validation matrix. If desired, our clients may be closely involved in either contributing to or monitoring of this process. In general, validation takes 2-4 weeks in order to gain information with regard to:
- The general utility of the protocol or synthetic access to the molecule of interest
- Tentative yield(s)
- Feasible synthetic route(s) and potential for further detailed optimization(s)
- Alternative strategies aimed at improving:
- Synthetic feasibility
- Yield(s) of the targeted materials
- Financial/material aspects of the work
- Potential to expand the procedure in order to conduct multiple compound library/ies and/or structure-activity relationship (SAR) studies
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Chemistry On Demand ™
platform offers access to ca. 15,000 heterocycles scaffolds that were used to generate1.5 M stock available compounds. In addition, our Company keeps developing new lead-like chemistries to yield an estimated 500 new templates every year. Our customers are invited to evaluate both ‘historic’ and new synthetic developments in order to select unique chemical space and preferred intellectual property (IP) mode (Template(TM) mode).
Validated chemistries can be further amended to meet your specific targeted or diverse needs in drug discovery. Both key intermediates and building blocks used in the syntheses are available as well.
Several key selection criteria for template/library production include:
IP status:
- Beilstein score
- SciFinder score
- Patentability
- Privileged structure search, literature annotation
Drug-/lead-like properties, Target/Pathway-Based Design :
- Target/interaction, pathway, cellular process relevance
- Solubility, MW, cLogP/D, tPSA, HBA, HBD, Fsp3, 20 add’l parameters
- Diversity considerations (various models available)
- Assay feasibility
- For selected compounds biological annotation in vitro, ex vivo and in vivo (‘Targeted Diversity'(TM) concept)
- Ligand Efficiency
- Customized parameters: ex., specific protein-protein interaction(s), allosterism, topology/charge distribution (spiro heterocycles, medium- and large-size rings, macrolide mimetics)
Chemistry Consideration:
- Proven synthetic feasibility
- Bioisosteric morphing
- Natural-like, amino acid- and peptidomimetics
- ADMETox parameters optimization
Our approach to chemistry services could be further customized to meet specific needs of your organization starting with diverse sets and finishing with selections that modulate specific cellular processes (ex., autophagy, endocytosis, receptor recycling). We work equally well with well-defined targets and pathways as well as with compounds that affect phenotypic change(s).
Please contact our team at chemdiv@chemdiv.com to discuss your specific needs and application.
Learn More about ChemDiv’s Chemistry on Demand Solutions
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Medicinal Chemistry and Library Screening
At ChemDiv, we realize that every medicinal chemistry endeavor is unique and determined by both scientific and business considerations. Although we do routinely use a combination of ligand- and structure-based methods to attain scientific goals of your project, a plethora of unique chemistry and biology tools are available to meet target-specific challenges. Our seasoned team of project managers and business developers will make sure that deliverables, timelines and financial aspects are in line with your expectations (see product profile). When conducting a structure-activity relationship (SAR) studies, we take into consideration the most current target-, pathway- and/or cellular process understanding as well as lead-/drug-like or Fsp3 character and ex vivo ADME/tox properties of synthesized SAR matrix. A variety of computational, structural biology, in vitro, cellular and phenotypic evaluation tools are available to guide you through this process. Proper choice of the screening platform and read-out technique(s) is determined by the nature of your biological target, desired product profile and timelines. Rapid assessment of compound’s PK/tox properties and relevant intellectual property (IP) profile allows you to expeditiously identify a lead candidate.
A typical medicinal chemistry team structure involves 1:1 PhD-to-BS/MS level scientists. On average, our team members amass 5+ years of experience in synthetic chemistry and structure-based drug discovery. Size and content of a team is dictated by the nature of your project. Team leaders are selected based on their extensive drug discovery track record in major Pharma and/or Biotech and sound communication/reporting skills.
MedChem design involves creation of new compounds for pharmaceutical, medicine and other applications.
HIT/ACTIVE IDENTIFICATION
With a total collection of 1.5 million small molecule library compounds available as solid samples and solution/dry film, our compound libraries are instrumental in your hit-finding programs. Notably, ca. 20% of this collection is designed to tackle specific targets, pathways, cellular processes or disease areas. These so-called focused small molecule libraries are assembled using available target- and ligand information, actual ‘wet’ biology combined with the most current compound library design trends including lead-likeness, Fsp3, soluble diversity, blood-brain barrier permeability, medium-/large-size and spiro-heterocycles, fragment-based, amino acid-, b-/g-turn-, peptide- and helix-mimetics, autophagy-, protein-protein interaction modulation and many other concepts. For the entire list of custom-built small molecule libraries, click on the focused compound libraries link.
Frequently, in silico docking of candidates, scoring of the resulting data and selection of the actual compound set using our internal Computer Aided Drug Design (CADD) platform is the first step in screening process. Our team of molecular, cell and structural biologists could help you with attaining the actual ‘wet’ 3D structure of a target or a relevant construct as an apo-protein or in complex with a ligand of interest. Fragment-based compound library, protein engineering, cloning, expression, purification, co/crystallization and x-ray crystallography are just a few components of this approach.
‘Traditional’ fluorescence- and radioactivity-based high-throughput screening (HTS) assays are strategically complimented with the state-of-the art phenotypic and high-content screening platforms. The latter is the key technology used at ChemDiv to study stem-cell (iPS/mES) differentiation and autophagy phenomena. Additional cellular ‘events’ of interest to our team include endocytosis and receptor recycling.
ChemDiv offers a variety of discovery chemistry services including in vitro, ex vivo, in vivo screening services, formulation development, IND package preparation and Phase I/II clinical studies. These could be implemented in either standalone or integrated drug discovery mode. Our multi-disciplinary team have an extensive experience in delivering late stage IND and clinical candidates in key therapeutic areas including CNS-, oncology-, CV/metabolic- and anti-viral/-infective diseases.
HIT TO LEAD DEVELOPMENT
A combination of SAR efforts, thorough ADME/tox evaluation and early PKPD/tox studies conducted in several rounds allows our team to narrow down chemical series that are selected as lead candidates and back-ups. Notably, the entire process is accomplished with a rigor common within the discovery chemistry industry. A desired product profile aimed at the optimized early safety/efficacy window is proposed, discussed with your team and implemented at this stage. Whether we focus on improving a specific parameter of your molecule(s) or progressing series from hit to a lead candidate stage, every step of this process is thoroughly documented, rationalized and communicated in terms of the accepted project flow metrics. A sophisticated panel of fragment-based, in vitro, cell-based, phenotypic, ex vivo and in vivo assays/platforms has been established to mediate this process. Importantly, our trained team of biologists can evaluate, validate and adopt your internal protocol(s) or a literature process in order to ‘industrialize’ an assay and to maximize screening success.
LEAD IDENTIFICATION
We follow a robust pharma metrics in order to identify lead candidates that feature favorable activity, pharmacology, selectivity, ex vivoADME and early PKPD/tox profile in order to advance them into the lead status. Rigorous assessment of screening compound’s efficacy in designated disease model(s), PK and sub-chronic/chronic toxicity in multiple species are integral parts of this effort. Our team is very sensitive to your request(s) for specific ex vivo/in vivo and bioanalytics study protocols. Moreover, we are delighted to further expand our understanding of the target’s engagement using modern ‘omics’ platforms including genomics, proteomics and metabolomics. Development of formulation, synergistic mixes and/or repurposing along with early assessment of lead’s intellectual property yields a robust patent positioning for your program.
TRACK RECORD
On behalf of our clients, we have developed agents targeting a plethora of targets and cellular processes. These include selective and dual kinase inhibitors, modulators of GPCRs, ligand- and voltage-gated ion channels, quiescent cancer cells, pro-inflammatory and proteasome signaling cascades, macro- and chaperone-based autophagy, developmental pathways (Hh/Smo, Wnt, TGF/BMP, NHR), stem cell differentiation, anti-viral and anti-bacterial agents. Multiple programs have culminated in the identification of leads and Phase I/II clinical development candidates. Every project of this nature involves detailed target- and financials/timeline analysis to culminate in a product profile. For specific examples, please contact our team at chemdiv@chemdiv.com.
Learn More About ChemDiv’s Quarter of a Century Experience in Discovery Chemistry Services
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Additional Chemistry Services
ChemDiv provides additional chemistry services.
ChemDiv supports comprehensive QC of all compounds; by NMR, HPLC/MS/UV and other options. ChemDiv provides 100% quality control for all compounds and guarantee more than 90% purity (+/- 5% accuracy). The purity accuracy is confirmed by 1H NMR and/or LC (UV)/ MS spectra in electronic format (MS TIF files) for all stock available compounds.Logistics and Formatting
With its extensive experience derived from establishing, maintaining and building the largest commercial compound collection, ChemDiv is the partner of choice for global logistics. We can guarantee smooth and fast progression on every project serviced. ChemDiv provides solutions for both compound acquisition and logistics support, including:
• Ordering of compounds from multiple suppliers (including thousands of sources in our global research network)
• High throughput QC, analytical and purification
• IT platform integration, data base procurement, mining and selection
• Library formatting, liquid and neat sample handling; dry / inert atmosphere
• Storage of chemical inventory; both automated and manual.
• Inventory and order tracking online, global in time distribution.ChemDiv’s network in this area includes 2,500 academic, biotechnology and pharmaceutical companies worldwide. The compounds can be formatted as a dry powder, dry film or frozen DMSO solution. The weighing can be done in umol or mg. Any handling solutions – multiple copies formatting, storage and dispensing on demand, partial shipments are available. All formats to be individually packed in bar-coded plates or vials. 96 well plates with detachable tubes, 384 well microplates, or 4 ml Amber glass vials are available in standard tare. Custom taring is also welcomed. Barcode formats 39/128 may be confirmed by customer. Delivery within 2-5 weeks for orders of any size; 2-3 business days for orders below 500 compounds. Post synthetic manipulation of compounds such as preparation of screening ready plates, dilution, storage and shipping can all be handled through CDI to support a seamless transition from concept through library preparation to biological data.
Follow-Up
Analog series
At ChemDiv we have developed a strategy combining the rigor of single compound synthesis in liquid phase with the high throughput of parallel synthesis and purification of combinatorial methods. One promising method enhancing the efficiency of compound synthesis is the use of multicomponent reactions, in which several building blocks are brought together in a single step. We applied this method for the Ugi, Biginelli, Passerini, Tsuge, and other reactions and developed several significant modifications of known multicomponent reactions. This approach gives our customers the opportunity to perform direct hit analogs search from stock available compounds.
Computational Chemistry
Our strategy for lead generation (focused) libraries design includes:
• Gathering project data (reference compounds, X-ray structure if available, literature patents)
• Computational chemistry (methods depends on target)
• Chemistry evaluation (investigate parallel feasibility)
• CCE database. Library ideas. SynthesisThe computational tool that we use on regular basis to narrow down large chemical space to a more relevant chemical space are listed here.
• ChemoSoftTM (CDI) www.chemosoft.com
• Smart Mining (CDRI)
• Cerius2 (Accelrys)
• Discovery Studio (Accelrys)
• NeuroSolution (NeuroDimension)
• ISIS Base (MDL)
• AutoDock (Scripps)
• Surflex (Biopharmics)
• MolSoft ICM (MolSoft LLC)The first two programs have been created here at ChemDiv/CDRI. The last one is our partner. All of these tools help maximize the chance of your finding an active compound using such familiar approaches as docking, searches based on 3D pharmacophore models and shape similarity (target-based strategy) and 2D fingerprint similarity, QSAR models, and substructure searches (in the ligand-based franchise). We also actively use a Neural Networks (NN) approach to assess libraries’ various parameters influencing ADME/PK characteristics such as potential interactions with P450, blood-brain barrier permeability, DMSO solubility, probability of being modulators of particular target classes, etc. For such libraries, using ChemoSoftTM, we can efficiently calculate prediction of their major physiochemical parameters, which are routinely used for the assessment of the compounds’ drug-likeness based on the Lipinski rules of 5 and certain ADME predictions.
Re-Supply/Re-Synthesis
All products can be supported by adequate replenishing, scale up. Re-supply is subject to ChemDiv’s current stock availability. Compounds re-synthesis (subject to the Customer’s confirmation) will be offered by ChemDiv if no adequate sample quantity is available for re-supply.
CDI comprehensive chemistry skill set includes:
• Pd-catalyzed coupling reactions (Sonogashira, Buchwald, Heck, Suzuki, Grubbs metathesis, etc. )
• Large-scale (100-150 g per run) (organometallic reactions, lithiation of aromatics and heteroaromatics , Cu, Mg, Zn, SM chemistry)
• Modern protective group strategies
• High-pressure and high-temperature reactions
• Microwave-assisted organic synthesis (Set of Biotage and CEM automated reactors)
• Solid phase supported library synthesis (Teabag technology)
• Liquid phase parallel synthesis (Solid phase catalysts, Scavenger resins, SPE purification)