Synthetic Chemistry Essentials for Biologists

(Heather Behanna, JMP Securities LLC)

Chemical structure patterns can help point to function and interactions.

  • Only a small part of chemical space is drug-like.

The core structures (scaffolds) of drugs tend to be heterocycles, which have these features:

  • Ring structures that can be involved in pi stacking and hydrophobic interactions
  • Heteroatoms (non-carbon atoms) for potential hydrogen bonding interactions
  • Heterocycles can interact with proteins through both hydrogen bonds and hydrophobic factors.

The core scaffold must have synthetic “handles” to make chemical modifications accessible.

  • Some scaffolds can be modified without changing the mechanism of action (but may have effects on ADME properties); some changes/substitutions will drastically affect activity (= privileged scaffold).

To obtain an initial hit, look for a starting point compound, with either binding or weak activity, that can then be optimized.

  • HTS involves using traditional assays to screen a library of compounds for activity against a target or phenotype.
  • Fragment screening involves looking for binding to a target using biophysical structure-based methods. But binding is not indicative of function.
  • Additionally, currently approved compounds or natural products can also be tested for activity against new indications.


  • Advantages:
    • Can screen hundreds of thousands of compounds in weeks.
    • Automated systems.
    • Novel in-house libraries.
  • Disadvantages:
    • Limited to the chemical space of the library.
    • “Red-flag” compounds.
    • Hits generally larger than optimal leads.
  • Functional assays alone are not sufficient for making a good drug – high potency compounds identified with HTS can be false positives.

Natural products can be adapted to produce hits.

  • Example: Genistein is an isoflavone which has been shown to have promise for several diseases. A derivative compound with small changes greatly improved cell viability while maintaining activity.

Hit criteria that are relevant regardless of how the hit is generated:

  • Potency in cell assays
  • Have synthetic handles for chemical modifications
  • Good ADME properties

The quality of the screened library strongly influences the chance of discovering drug-like suitable hits. Libraries should be chosen for the same reasons that compounds are chosen later in development.

  • Fragment libraries tend to have better properties as hits than HTS libraries.
  • Interdisciplinary teams are best for hit evaluation.
  • Look out for “red flag” compounds.

Hit-to-lead refinement

  • For HTS, start with many compounds to find what’s important and narrow down to an essential scaffold. Then, build that scaffold back up with medicinal chemistry to have the right properties.
  • For fragment based screening, start with the core fragment and build up from binding to activity, increasing potency as a drug.
  • Increase potency and selectivity, increase in vivo efficacy.
  • Prioritization is key!

Criteria to become a lead – the compound:

  • Must show structure-activity relationships (SAR) – not a flat landscape.
  • Have synthetic handles for modifications. It should also be simple (have fewer stereocenters) to minimize cost.
  • Show activity in cellular assays (or in vivo), reach cellular target.
  • Show lead-like ADME properties to expedite and simplify further optimization.

Medicinal chemistry refinement is an iterative cycle: from synthesis of compounds to screening of activity/ADME properties to data analysis (SAR trends) and refinement of criteria.

  • Initial synthesis of many compounds will enable better understanding of trends. There will also be fall-backs if a particular compound fails to show the expected in vivo pharmacology.
  • Different compounds may show similar activity but vary greatly in selectivity or ADME properties. Alter synthetic handles to explore the chemical space with various substitutions.
  • Different compounds may show similar activity but vary greatly in selectivity or ADME properties. Alter synthetic handles to explore the chemical space with various substitutions.
  • Parallel synthesis of groups of compounds made by facile reactions from a common intermediate allows the quickest turnaround response to biological data.
  • Example case study for library design:
    • Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides. Gillespie RJ et al. Bioorg Med Chem. 2009 Sep 15;17(18):6590-605.
  • Chemistry efforts are led by biological results. Constant communication between team members of different disciplines is key to overcoming obstacles.

Factors to consider for shift to synthesis of active pharmaceutical ingredient (API) – making large amounts of one compound.

  • Syntheses should be scalable from grams to kilograms.
  • Syntheses should avoid metals. Metal impurities must be minimal in the final compound. Keep in mind that metal removal can be very expensive.
  • Syntheses should be purified easily.
  • Salt forms are often used as APIs due to the greater stability and solubility.
Basics of high throughput screening (HTS): Bridging chemistry and biology >