Stereoisomers • Stereoisomers are isomers with the same molecular formula AND the same structural formula, but a different arrangement of atoms in space. • Geometric isomers: • If a pair of stereoisomers contains a double bond, cis and trans arrangements can exist: • cis: substituents are on the same side of the double bond • trans: substituents are on opposite sides of the double bond
Geometric isomers • Geometric isomers have: • different physical properties, including polarity, boiling point, melting point, and solubility • Different chemical properties, and thus different pharmacological effects • Ex. Cisplatin • Square planar molecule, NH3 groups are either on same side of the square or opposite sides
Optical isomers • Optical isomers: • Different from geometric isomers: • The molecules are chiral (asymmetric, meaning that there are four different groups around a central atom) • The isomers are non-superimposable mirror images of one another • Each isomers differs in its optical activity (the ability to rotate the plane of polarized light) • One isomer (enantiomer) rotates the plane of polarized clockwise (+ form), the other rotates it counterclockwise (- form)
Optical isomers • An equimolar mixture of both enantiomers (racemic mixture) will not rotate the plane and is said to be optically inactive • Drugs from natural sources are usually chiral and are generally found as a single enantiomer • Ex. Penicillin V • Opposite enantiomer can only be produced artificially and is pharmacologically inactive
Optical isomers • Synthetic drugs, when chiral, are usually produced as racemic mixtures • Ex. : Ibuprofen • One enantiomer is pharmacologically inactive • Drug still produced as a racemic mixture to reduce costs • Thalidomide • One enantiomer alleviates morning sickness, the other can cause birth defects • Unknown before it was prescribed in the 1970’s • Racemic mixture (“bad” and “good”enantiomers) can still be sold as a treatment for leprosy
Chiralauxiliaries • Synthesis of non-racemic mixtures is difficult, as both enantiomers are chemically identical in relation to non-chiral reagents • “chiral auxiliaries” (helping-hands) are used to produce a desired enantiomer from a non-chiral molecule • Attaches itself to non-chiral“building block” to create the stereochemical conditions necessary to force the reaction to follow a certain stereospecific path • Auxiliary can be removed and reused once the desired enantiomer has been formed • Eliminates the need to separate a racemic mixture
Importance of beta-lactam ring action of penicillin The beta-lactam ring is circled in orange. Structure of Penicillin: • 4 membered square ring with bond angles of 90o • Ring consists of 1 N atom and 3 C atoms • Ring is strained and so very reactive Action: • When the beta-lactam ring comes into contact with bacteria, • the ring "opens", • and covalently bonds to the enzyme transpeptidase • that is used to synthesize the bacterias cell wall. • The enzyme's action is therefore blocked, • the bacterias cell wall is weakened, • and the bacterium eventually bursts.
Comparison of structures: Heroin and Morphine Comparison of structures: • Identical except the functional groups on the left. • Heroin has two ester groups which are less polar. • Morphine has 2 polar hydroxyl groups Solubility/Potency • Heroin is insoluble in water because it is less polar due to the presence of ester groups that can't form hydrogen bonds with water. • Heroin can therefore be transported to the less polar/lipid parts of the body like the brain and nervous systems. • Heroin will reach higher concentrations in the brain (due to is less polar nature) and thus will appear more potent and produce greater analgesic effects, which in turn, makes it more addictive. • Morphine is soluble in water because the polar hydoxyl groups can form hydrogen bonds with water and will penetrate the brain less easily than heroin.
Explain the increases potency of diamorphine (heroin) compared to morphine Although diamorphine (heroin) and morphine share the same basic structure, heroin is more potent and thus more addictive because of its polarity due to the presence of its functional groups. Heroin (left) Morphine (right)
Combinatorial chemistry • As drug R & D is very costly and time-consuming, most drug research begins with a “lead compound,”(not lead as in metal, but “leed”)whose main structure is left unaltered but other parts are changed to produce more effective drugs. • Combinatorial chemistry (combi-chem) involves creating a large number of molecules and quickly testing them for desirable biological activity • Sometimes compounds are “virtually tested” by computer simulation • Combi-chem involves reacting a set of starting materials in all possible combinations • Uses same methods as basic organic synthesis, but uses technology and computers to make very large libraries of related chemicals • Increases the chances of finding better drugs
Parallel synthesis • Libraries of a vast amount of related compounds are produced using robotics to perform repetitive work (ex. adding a fixed volume of a substance to a collection of chemicals) • Products of these reactions are then tested, without animals, by studying their effects on enzymes
Solid-phase synthesis • Combi-chem began in the 1960’s • Most importantly: Solid-phase synthesis: • Peptide bond is created between two amino acids through a condensation reaction: • Solid-phase synthesis allows for the rapid creation of a large number of polypeptides by employing the use of plastic beads
Solid-phase synthesis • “linking group” is attached to a plastic bead • In vessel 1, amino acid A attaches to linking group, eliminating an HCl (Cl from linking group, H from OH group of acid portion of AA) • Bead is placed in Vessel 2, where it attaches to amino acid B via a peptide linkage • Process continues with any number of amino acids
Solid-phase synthesis • Procedure can be extended so that the first step reacts two amino acids, A and B, to produce bead A and bead B • These can be split into separate containers so that each now contains beads A and B, in a half and half mixture • In the second stage, one container is reacted with amino acid A to produce bead A-A and bead B-A • the other container is reacted with amino acid B to produce bead A-B and bead B-B • This two amino acid, two stage process produces 4 (22) amino acids (A-A, B-A, A-B, and B-B) • Starting with 3 amino acids in a 2 stage process would produce 32 (9) peptides, 10 amino acids in a 4 stage process would produce 104 (10,000 polypeptides) etc. • A large polypeptide library can therefore be quickly produced • Process can also be extended to other molecules besides peptides to produce very extensive chemical libraries
http://ibchemistrymedicinesanddrugs.wikispaces.com/D.8.3+Drug+Actionhttp://ibchemistrymedicinesanddrugs.wikispaces.com/D.8.3+Drug+Action • http://ibchemistrymedicinesanddrugs.wikispaces.com/D.8.4+Drug+Action • http://www.chemactive.com/ppt/ib/Option_B_-_Medicine_and_Drugs.ppt