Stereochemistry's Role in Drug Synthesis: Chiral Compounds and Biological Effects, Summaries of Engineering Chemistry

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NAME: JACOB ABRAHAM

CLASS: FE COMP A

ROLL NO: 201105020

IMPORTANCE OF

STEREO CHEMISTRY

IN

DRUGS/MEDICINE

SYNTHESIS

SERIAL NO: CONTENT PAGE NO:

1 INTRODUCTION 2

2 LITERATURE 3

3 LITERATURE EXPLANATION 4 - 10

4 CONCLUSION 11

5 REFERENCE 12

1 | P a g e INDEX INTRODUCTION

The following topics will be discussed further in this document.  Stereo chemistry  Isomerism and its types  Chirality and other important terms  Importance for drug design  Case studies of some drugs and their evil twins

o

 STEREO CHEMISTRY Branch of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. Stereochemistry focuses on stereoisomers , which by definition have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space. For this reason, it is also known as 3D chemistry—the prefix "stereo-" means "three-dimensionality. [ref B ]  ISOMERS AND ITS TYPES  CHIRALITY AND OTHER IMPORTANT TERMS A molecule containing a carbon with four different groups results in a chiral molecule. Chiral compound is a compound that is optically active ( can rotate plane polarised light clockwise[+] or anticlockwise[-] ). Chiral compounds are non-superimposable mirror image like our two hands. [ref G] Naming Conventions The optical isomers are named:  By configuration: 1.R- and S & 2.CIS and TRANS

1. 4 grps bound to tetrahedral asymmetric C atoms, which are ranked.  Grps oriented in clockwise fashion = R isomer  oriented anti-clockwise = S isomer
2. 2 similar / higher priority groups attached the carbon  on the same side = Cis isomer   on the opposite side = Trans isomer LITERATURE EXPLANATION

The enzymes which catalyze most reactions in body are stereoisomer specific. This is because these enzymes themselves being biomolecules are chiral. This can be explained further. We can see that there is an enzyme with three binding site for an amino acid. If the amino acid was in a non-enzymatic reaction, the stereochemistry is selected by bulky groups’ positions and we will get all the stereoisomers even though one isomer will be preferred. But in an enzymatic reaction, the amino acid has to bind with the specific binding site before catalysis. Thus enzymatic reaction is always stereoisomer specific (other isomers of the molecule may be catalysed by the enzyme if the enzyme has additional binding site, but even then the catalysis is usually weak). The biological receptors (including enzymes) for drugs are chiral. Therefore they respond to only one isomer of a ligand/drug. The isomer with desired biological activity is called eutomer and the other isomers are called distomer. [ref I]  CASE STUDIES OF SOME DRUGS AND THEIR EVIL TWIN

1. Thalidomide HISTORY = story of the drug Thalidomide is heartbreaking, but it illustrates why we pay so much attention to stereochemistry.  The compound was identified in the 1950s as a neurologically active molecule that had the ability to quell morning sickness in pregnant women. After the drug began to be marketed, children born to women taking it displayed horrific birth defects--often extremely shortened arms and hands that were not functional. The drug was pulled from the market after these problems, along with death rates approaching 50%, were reported. This disaster helped lead to the creation of the modern drug testing and approval regime in the United States and Europe. The part of the story that pertains to stereochemistry is that the original drug was made and sold as a

mixture. These are mirror images of each other, as you can see; they are not identical. researchs revealed that only the form on the right (the "R" form) was therapeutically active; the one on the left (the "S" form) was not only ineffective, it was the source of the birth defects! STEREO CHEMISTRY =(racemic mixture) Thalidomide has just one chiral atom and so exists as two enantiomers. Thalidomide exists in two mirror- image forms: it is a racemic mixture of (R)- and (S)- enantiomers. The (R)- enantiomer, shown in the figure, has sedative effects, whereas the (S)-isomer is teratogenic. Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective. BIOLOGICAL EFFECTS = Thalidomide drug exist as optical isomers,=Enantiomers (R) and (S) •(R) effective against insomnia and morning sickness •(S) teratogenic, birth and limb defect [ ref C]

2. Methamphetamine HISTORY = Methamphetamine was discovered in Japan in 1919, but it really caught on during World War II when combatants used it to go without sleep and stay alert. The Japanese passed out “flyer’s chocolate” to their soldiers, and then had to face an epidemic of methamphetamine addiction after the war. Hitler himself used it intravenously and developed Parkinson’s symptoms. STEREO CHEMISTRY = Methamphetamine is a chiral compound with two enantiomers. Chiral molecules have non-superimposable mirror images. As you’ll see, the two compounds are very different medically despite having only a subtle structural difference.  L-methamphetamine is found in Vicks Vapor Inhalers.  D-methamphetamine the street drug known as crystal meth(highly addictive). BIOLOGICAL EFFECTS =

introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others. STEREO CHEMISTRY = The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images. This racemic mixture can be separated into its optical isomers_ Optical isomers were given their name because they were first able to be distinguished by how they rotated plane-polarized light_: levoamphetamine and dextroamphetamine. BIOLOGICAL EFFECT = Dextroamphetamine :- is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), sometimes prescribed off-label for its past medical indications, such as depression and obesity. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Levoamphetamine:- is a central nervous system (CNS) stimulant known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. [ ref D]

5. OTHER EXAMPLES [ref H]

A. ijpsr.com/bft-article/stereochemistry-and-its-role-in-drug-design B. wikiepedia.org/stereo-chemistry C. youtube.com/minute earth D. researchgate.net/publication/ Stereochemistry_And_Its_Role_In_Drug_Design E. chem.libretexts.org F. slideshare.net/AZMINMOGAL/stereochemistry G. youtube.com/TED ed H. slideshare.net/case-study-of-stereochemistry-and-drug-design I. sciencedirect.com J. Book: Basic and advanced stereo chemistry : K S Mukherjee & Jerry march REFERENCES