Genotoxic Potential Alert Chemical Structures

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Genotoxic Impurity

Genotoxic impurities (GTI’s) are intermediate, reactive products or degradants formed during the synthesis of drug substance, formulation of the drug product, or storage of drug substance or drug product. Genotoxic impurities have the potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer.

Genotoxic Potential Alert Chemical Structures:

Chemical structures are helpful to plan to classify compounds into their types that will alert them to potential material. The computer software’s e.g., MultiCASE’s M case, Accelrys’s Topcat, or LHASA’s DEREK is available for forecasting the probable toxicity of drug impurities on the basis of it is chemical structure. It is predictive and may not be factual, they will give hint of which one would be confirmed from the toxicity studies. Performing Ames bacterial mutagenicity testing after software provides a structural alert. Results from the Ames test are considered more definitive than the in silico data.

Following are the structural alerts present in drugs which are supposed to be genotoxic property:

  1. Alkylating agents: The main concern with alkylators is the possibility of alkylating DNA bases on N-7 of guanine and N-3 of adenine, while other biomolecules also may be affected. Alkylation provides information about forming bonds to aliphatic carbon atoms. Also, there is the chance of forming undesirable alkylating agents during synthesis. When a salt counterion of a basic intermediate or drug molecule (e.g. HCl or similar salt) reacts with alcohol used as a solvent to form alkyl halide.

There are number of structural subjects that give surge to alkylating capability and these are further sub-categorised below.

  • Alkyl halides:

These include alkyl chlorides bromides and iodides. Reactivities are in the order I > Br > Cl. Hence iodide salts are sometimes used to catalyse a reaction with alkyl chlorides, since I is a good nucleophile that displaces the chloride. The resulting alkyl iodide is a more powerful alkylating agent because iodide is a much better leaving group than chloride.

  • Alkyl sulfonates: Sulfonate anion is very good leaving group, making esters good alkylating agents. Generally used alkyl sulfonates are esters of methanesulfonic acid (mesylates), benzenesulfonic acid (besylates) and p-toluenesulfonic acid (tosylates). In addition, sulfonic acids are regularly used to form salts of bases for purification of API or intermediates form of the drug for reasons of bioavailability. Interactions of these with residual alcohols may be a cause for concern.
  • Dialkyl sulphate: Dimethyl sulfate and diethyl sulfate are commonly used as methylating and ethylating agents. There are chances of an increase in sulfate salts to these compounds in the presence of methanol or ethanol must be considered.

2. Hydroperoxides: Hydroperoxides result in oxidative damage to DNA.

3. Fused tricyclics: These compounds are able to intercalate between the coils of the DNA double helix.

4.Substituted purines and pyrimidines: Replaced purines and pyrimidines can themselves be inaccurately merged into the DNA sequence, leading to mutations.

5.Epoxides: Ring-opening of epoxide results in a reactive ion that can alkylate DNAQuinolines can be metabolished to form an epoxide on the nitrogen ring.

6.Aziridines: The strained ring in aziridines makes them reactive, with ring-opening under attack from any nucleophile to create a new nucleophile–carbon bond. Aziridine rings can be formed from the intramolecular substitution of a halogen atom by the nitrogen in nitrogen mustards.

7.Reactive amines: Aromatic amines (anilines) can be activated in vivo to form reactive amines. These are nucleophiles and may attack DNA, forming covalent modifications. Aromatic nitro compounds can be metabolized and form reactive amines.

Conclusion:

Chemical structure with listed functional groups known to be involved in reactions with DNA that could be used as structural alerts. These functional groups were categorized into aromatic groups. These are reported as genotoxic impurities which should be removed or in cases where it is inevitable, these should be within limits to prevent the toxicity. Need to develop different API purification techniques for removal of genotoxic impurities to the stringent levels.

References:

  1. International Conference on Harmonization, ICH M7 (R1): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 31 March 2017.
  2. European Medicines Agency, Guideline on the Limits of Genotoxic Impurities, EMA/CHMP
  3. International Conference on Harmonization, ICH Q3A (R2): Impurities in New Drug Substances: ICH, Geneva, Switzerland.
  4. International Conference on Harmonization, ICH Q3B (R2): Impurities in New Drug products: ICH, Geneva, Switzerland.
  5. International Conference on Harmonization, ICH Q3C (R4): Impurities: Residual Solvents: ICH, Geneva, Switzerland.
  6. Liu DQ and Korda AS. Analytical challenges in stability testing for genotoxic impurities. Trends Anal Chem. 2013;49:108-117.
  7. Baker A. Development of a strategy for analysis of genotoxic impurities. Genotoxic impurities, strategies for identification and control. Wiley Publication.
  8. Analysis of Drug Impurities, Edited by Richard J. Smith and Michael L. Webb.

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