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35 Cards in this Set
- Front
- Back
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What does a large Ka represent? |
A strong acid |
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What does a small Ka represent? |
A weak acid |
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What does a small pKa represent? |
A strong acid |
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What does a large pKa represent? |
A weak acid |
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What are the features of ring A of Benzodiazepines? |
• Ring A involved in pi-pi stacking in the receptor protein • An electronegative group in position 7 markedly increases the functional anxiolytic activity • Substituents in 6, 8 or 9 positions decrease anxiolytic activity • Exchanging ring A for a heterocyclic ring leads to lower anxiolytic activity |
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What are the features of ring B of Benzodiazepines? |
• Alkylation of the amide nitrogen in position 1 with sterically undemanding groups does not affect activity significantly • A proton accepting group in position 2 of Ring B is essential, coplanar with Ring A • Substituting sulfur or oxygen in position 2 does not affect anxiolytic activity significantly • Substitution on the methylene group at position 3 has no effect on anxiolytic (agonist) activity but decreases antagonist activity • The stereochemistry of hydroxylation at position 3 does not affect activity • The stereochemistry at position 3 may be important for steric interactions at the receptor with one enantiomer being favoured• The 4-5 C=N bond is essential for in vivo activity |
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What are the features of ring C of Benzodiazepines? |
• Ring C may contribute to steric or hydrophobic interactions • Substitution at position 4’ is unfavourable due to steric interactions • Substitution at position 2’ is not detrimental to agonist activity |
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Which enzyme catalyses the aliphatic hydroxylation/N-dealkylation of Diazepam to Temazepam? |
CYP3A4 |
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Which enzyme catalyses the aliphatic hydroxylation/N-dealkylation of Diazepam to Nordazepam? |
CYP2C19 |
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Which enzyme catalyses the aliphatic hydroxylation/N-dealkylation of Nordazepam to Oxazepam? |
CYP3A4 |
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Which enzyme catalyses the aliphatic hydroxylation/N-dealkylation of Temazepam to Oxazepam? |
CYP2C19 |
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Advances in Technology |
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What is Combinatorial Chemistry? |
• A process where groups of starting materials are reacted together to make every available product • Mixtures of products are obtained – a library • Useful for making very diverse mixtures of compounds with drug-like properties for screening • One set of starting materials may be fixed on a solid support – solid-phase synthesis • Can be totally automated, increase productivity • Introduces diversity in lead compound structure • Rational versus Irrational drug design |
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What is a Compound Library? |
• A collection of compounds prepared for testing • A library contains very little of each compound • Several types of library can be prepared: • Virtual: in silico • General: no bias for a target • Discovery: a library with drug-like features • Focused: designed to inhibit a target family • Targeted: designed to inhibit a specific target |
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What is Orthodox Synthesis? |
A + B ----> AB |
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What is Combinatorial Synthesis? |
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Making a Simple Library |
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What is 'Mix and Split' Library Synthesis? |
-Substrates are attached to a solid support -Reactions are driven to completion by using excess reagent -Screening issues -Positive results must be deconvoluted |
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What is Solid Phase Organic Chemistry? |
-The development of automated solid-supported peptide synthesis revolutionised peptide research -The automated methodology has been adapted to make many peptides in parallel -All of the chemistry required has been worked out so combinatorial synthesis of peptides is easy -The methodology can also be applied to the synthesis of any small-molecule library using combinatorial chemistry on a solid support |
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What happens in Solid Phase Organic Chemistry? |
-Each substrate is attached to a polymer bead -All reactions are driven to completion by using an excess of reagent -The final products are separated easily from the reaction mixture by filtration -By-products and excess reagents can be washed off the solid support, leaving pure product to be cleaved from the bead |
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What rules should be obeyed in solid phase organic chemistry? |
-The polymeric support must be insoluble and inert to the reaction conditions employed -The means of linking the substrate to the solid support must allow efficient and selective cleavage of some or the entire quantity of product from the solid support -A protecting group strategy must be used which allows selective protection and deprotection of all reactive groups in the building blocks ot be used and the supported substrate. |
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What are the most widely used solid supports in solid phase organic chemistry? |
Cross-linked polystyrene beads |
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What can limit the range of possible reactions in solid phase organic chemistry? |
The local evironment around the polystyrene bead |
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What polyamide provides a more suitable environment for peptide synthesis? |
Sheppard's resin |
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Which resin has polyethylene glycol residues tethered to polystyrene beads? |
Tentagel resin |
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What is the surface environment of Tentagel beads like? |
Hydrophilic, but also like a polar organic solvent |
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What does the linker group provide? |
A means by which the substrate is attached to the polymer bead |
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What does the linker dictate? |
What chemistry the growing substrate will withstand, the conditions required to release the library from the solid phase, and what functionality will be revealed. |
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What is Merrifield resin? |
A resin developed for peptides: -Requires HF to cleave the product from the bead -Reveals CO2H |
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What is the Wang linker? |
-Suitable for a base-labile protecting group strategy -Requires 1%-95% TFA for cleavage -Reveals CO2H |
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How do you screen compound libraries? |
-Screen the library in solution: -Must cleave all compounds from the support -Possibility of false or misleading hits -Must resynthesise all compounds in an acitve library -Screen Individual compounds in solution: -Separate the beads manually -Requires a method for identifying active structures -Screen compounds still attached to the support -Colorimetric/fluorimetric assay -Support can restrict the conformation of the product |
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What is hit structure determination? |
-The active hit must be prepared on a larger scale once activity has been found -Structure determination can be the rate-limiting step -The structure of the hit would be determind whilst the compound is still anchored to the solid support -Nanomolar quantities ofb the hit cannot be characterised easily using spectroscopy so some other methodology, chemical or otherwise, is required to trace the hit structure |
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What are Matric Metalloproteinase (MMP) enzymes? |
-A family of zinc-dependant enzymes -Degradation and remodeling of the extracellular matrix -Important therapeuitc targets with indications in cancer, arthirits, autoimmunity, and cardiovascular disease -Selectivity is important for therapy -Diketopiperazine (DKP) enzyme inhibitors chosen as lead compounds following de novo drug design -Solid-phase combinatorial synthesis chosen as a route to develip a diverse array of analogues for screening |
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What is the most selective inhibitor for collagenase 1? |
PhCH2 |
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What is the best candidate for optimisation for Gelatinase B Inhibitor? |
C6H11CH2 |
