Designing safer chemicals

examples of commodity chemcials that have leasd to adverse side effects

• PFAS: widely used commodity chemical (packaging, coatings), but very slowly biodegradable. Now it can be found everywhere, and can accumulate in the body leading to health risks.

• DDT: insecticed used to spread on crops and reduce malaria. however it was found to cause reproductive problems in a certain kind of birds leading to its ban. it is also very slowly biodegradable

  • example of intended spillage

• CFCs chlorofluorcarbons: once considered a safe refrigerant and aerosol propellants (replacing toxic ammonia). But because of its slow degradation, it allowed them to accumulate in the atmosphere damaging the ozone layer (Cl radicals act as catalyst for O3 to O2 conversion). although now banned, ozone layer is still recovering

two main approaches of sustainable chemistry

1. designing safer synthetic pathways to the same or similar chemicals

2. designing new/safer chemicals themselves

   1. preferable also through a greener patwhay over traditional alternatives

12 prinicples of green chemsitry mainly focus on approach 1, but not sufficient to solve DDT or PFAS problems therefore sustainable chemistry should focus more on approach 2

designing safer chemicals

using SAR and synthesis to find the optimum relationship between toxicological effects and efficacy of intended use

although optimum cannot be determined form scientific reasoning but only provide insight. so it’s determined as a society (side effects more accepted for anti drug than pain killer)

_{•‘Domestication’ of chemistry}

_{like a wolf has domesticated to dogs. we still use dangerous chemicals we have to take precautions for. but in an ideal situation, we should be able to safe chemistry in our kitchen for instance.}

Starting points of designing safer chemicals

1. need for new chemical with specific function - come up with structural design - new chemical that is safe and effective

2. start from existing effective chemcial (that may not be safe or green) - redesign - modified chemcical that is safe and effective

what’s new? (new way of approaching this)

Like SAR with respect to biological activity and toxicity has always been important in medicinal chemistry, this knowledge should be extend to the design of all chemcials.

Should lead to a new toxicological chemist that combines the knowledge of:

• industrial chemist (efficacy)

• medicinal/pesticide chemist (awareness of side effects)

• also have broader environmental check (not only consider human health.

design strategy

1. define characteristics to guarantee efficacy (what should the comoun do?)

2. define molecular characteristic responsible for efficacy (how should compound induce effect?)

3. design and redesign chemcial avoiding adverse effects on human biology or environment

external vs internal considerations for designing safer chemicals

External (have nothing to do with the metabolism of the organism on which we study the adverse effects)

• distriubition into the environment

• uptake by organisms

• routes of absorption by man, animal and aquatic life

• reduction/elimination of impurities

internal (have to do with the metabolism of the organism on which we study the adverse effects)

• facilitate detoxication (easier excretion by the body)

• avoid direct toxication (direct toxic effect)

• avoid indirect biotoxication (creation of toxic metabolites)

toxicity of benzene (biotoxication)

benzene itself is not toxic, it is a very stable inert molecule. However in the body, benzene is metabolized to facilitate its excretion. since it is very apolar, is does not dissolve well in aqueous media such as urine. the body converts into more compounds to facilitate this.

this occurs through oxidation reactions catalyzed by cytochrom enzmes that use oxygen as a reagent. This can lead to the transformation of benzene to epoxide intermeidates that are strongly electrophilic. These are susceptible to nucleophilic attack by nucleophilic gorups on DNA, RNA or proteins so alkylation can occur. This can lead to damage of genetic material or deactivate enzymes leading to loss of protein function and toxic or carcinogenic effects

External considerations:

• Environmental distribution/dispersion

Factors:

• volatility/ density/melting point

  • more volitile compounds spread more easily

• solubility

  • lower sol means slower spread into the environment

• persistnce (susceptibility to biodegradation)/degradation, main routes:

  • oxidation

  • hydrolysis

  • photolysis

  • microbila degradation (by microorganisms, diverse but mostly oxidation and hydrolysis)

this can result in conversion to biologically active (toxic) or incactive (harmless) substances

eg. DDT —>DDE

External considerations:

• uptake by organisms

Main parameters

• volatility (breathing)

• lipophilicity (LogP = Coct/Cwater)

  • important paramater in drug discovery

  • measured by my putting compound in equal mixture of octanol and water, shaaking it, allowing phase separation and measure conc in both layers

  • higer LogP = higher conc in octanol = higher lipophilicty

    • why octanol as it still contains an alcohol (polar)?

    • because this additional polarity was agreed to resemble human tissue the most which is not purely hydrophobic

• Molecular size

  • large molecules are less likely to be taken up

  • may require degradation e.g. hydrolysis of ester but depens on other factors

    • pH

    • digestive enzymes (does not mean every molecule with ester or amide is hydrolysided, it still has to fit into the pocket)

External consideration:

• routes of absorption by man, animals, or aquatic life

• skin

• eyes

• lungs

• gastrointestinal tract (from mouth to an*s)

• gills for fish or other species specific routes

External considerations:

• Reduction/elimination of impurities

• presence/generation of impurities of different chemical classes

  • more easily removed because different physical and chemical properties

• presence/generation of toxic homologs

  • harder to remove

• presence/generation of geometric isomers or stereoisomers

  • very difficult to remove

  • R- vs S-thalidomide was used as a drug to treat morning sickness during pregnancies but was banned because it caused birth defects (like arms missing) because of one of the isomers (S)

Internal considerations

• facilitation of detoxication

facilitate excrection (mostly via urine)

• select more hydrophilic compounds

• facilitate conjugation or acetylation

  • body can attatch sugar moieties (highly polar) to compound it wants to eliminate so it’s more readily excreted

  • so chemist can provid a handle to which this can occur

facilitate biodegradation

• introduce functional groups that are susceptible to smooth fragmentation, hydrolysis, oxidation, reduction,…

facilitation of biodegradation example

Laundry softeners

• they are cationic detergents with a polar cationic head and a hydrophobic tail

• Use

  • The water used to wash our clothes contains ions like Mg2+ or Ca2+ that have affinity for the fabric, if this occurs to a certain extent the fabric becomes hard

  • so in the final cycle of washing cationic detergents are added that replace the ions from the fabric so it becomes soft again

• cationic detergents are more toxic than anionic ones (soaps) because they affinity for DNA

• they don’t have any real FG the body can use to metabolise it

• Solution: somewhere in the chain put an ester so the body has a handle for hydrolysis, it is than converted into an alcohol which is harmless and and NR3+-COOH which is polar and is more easily excreted

• but in industry it is hard to change the process used to make it in a competitive market (want to keep it cheap)

  • industry doesn’t like change

Internal considerations

• Avoidance of direct toxication

• Selection of appropriate chemical class or parent compound

  • eg. if you discover an insecticide that is very similar in structure to corticoids (a type of steroid) this should ring a bel

  • they are structurally very similar to hormones whcich act at small concentrations in the body to spreading them in the envirionment at large scale is a bad idea

• selection of fucntional groups

  • avoid toxic FGs (like cationic FGs like micheal acceptors)

  • planned biochemical elimination of toxic structual elements by incorporating elements that facilitate this metabolization (without making a more toxic metabolite)

  • structural blocking of toxic groups (sterically shield cationic groups to prevent nucleophilic attack)

  • pot toxic group at alternative molecular site

Internal considerations:

• avoidance of indirect biotoxication

• avoid chemicals with known activation routes

  • aromatic amines

  • unsaturated bonds

• sterically block bioactivation

  • but bulky groups around FG’s susceptible to bioactivation

phases of Toxicity

1. exposure phase

2. toxicokinetic phase

   1. absorptions

   2. distribution

   3. metabolism

   4. excretion

      1. (ADME)

3. toxicodynamic phase

   1. chemical and biomolecular interactions with target tissue

4. toxic effect

Absorption

skin

• designed to not allow chemicals from the outside to get in

• high thickness

• low surface area

• low bloodflow

gastrointestinal tract:

• large surface area to allow exhange between lumen of intestins and blood

• lower thickness

• higerh bloodflow

lungs

• also high surface area designed to allow exchange of O2 and CO2 ( and other chemcicals)

• very thin

• very high bloodflow (allows easier exchange)

physicochemical parameters of importance for absorption

• molecular weight and size

  • larger molecules are more diffiicutl to absorb

• dissociation constants

  • gastrointestinal tract is optimised for absorption of certain chemcials like amino acids, these are zwitterionic so dissociation cte’s can be of importance

• particle size

  • asbestos is small and easy to enhale

• aggregation state

  • liquid, solid, gas (easier to enhale)

• lipophilicity

  • octanol/water partition coefficient

Lipinksi’s rule of five

Get an idea about the oral availiability of biomolecules

• no more than 5H-donors

• no more than 10 H-acceptors

• Mw lower than 500 g/mol

• LogP < 5

rules are designed to penetrate barriers but we want the opposite effect for toxicity. therefor we can apply the same rules but use them oppositely

molecular modifications to reduce absorption from the skin

• polar, ionised, water soluble, low lipophilicity (rather than the opposite

• solids rather than liquids

• increase particle size or increase molecular weight and particle size

molecular modifications to reduce absorption from the lungs

• less volatile (lower vapour pressure, higher boiling point)

• higher melting point

• less water soluble ie. higher lipophilicity (opposite to skin)

  • lung has a really thin membrane, while the skin has a thick hydrophobic membrane that would require hydrophobic compounds to get through

  • since the lung’s is thin, so the first step of the drug is to dissolve in the thin aqueous lining fluid in the airways before it can enter through the lipophilic membrane, increasing lipophilicity slows this process

• bigger particle size > 5 µm

Molecular modification to reduce absorption from the gastrointestinal tract

• increase particle size

• increase molecular weight >500 g/mol

• logP > 5

  • opposite of lipinski and absorption in via the skin

  • higher lipophilicity means more difficult uptake

• high melting point > 150°C (for non-ionic substances)

• keep substance unionized (or highly ionized)

  • in contrast to zwitterionic compounds

    • these are in between unionized and highly ionized and are thus abosrbed better (like AA’s)

    • also faty acids are weakly acidic and partially ionised and also abosrbed

    • this is not what we want for toxicity

  • thus unionized or highly ionized molecules are less likely to pass

Remark: difficult uptake becomes more and more problematic in medicinal chemistry

Drug candidates become more and more complex as the simple ones have already been investigated

they are more complex, bigger, and don’t abide lipinski’s rules anymore and are therefore less bioavailable

Understanding of toxic mechanism

• very common pathway of toxicity is through the compound acting as an electrophile

• the electrophile can react with nucleophilic groups present in the biological system

  • thiol of cysteine in proteins

  • amine(like) groups in purines or pyrimidines in DNA or RNA

  • oxygen atoms of purines or pyrimidines in DNA or RNA

• main effects

  • cancer

  • hepatotoxicity

    • liver (main source of detoxication)

  • hematotoxicity

    • blood

  • nephrotoxicity

    • damage to kidney

  • developmental toxicity

  • reproductive toxicity

Understanding of toxic mechanism

Electrophiles

• electrophile enters the body