Chemistry Biology Materials

첨단화학의 이해

SynthesisMake me a molecule

Biology Materials

Chemistry

첨단화학의 이해DNA, Genes, and Proteins

첨단화학의 이해Genomics, Proteomics and Chemical Genetics

Genomics

Proteomics Chemical Genetics

Gene Sequence:- ~30,000 genes- unable to identify therapeutic

targets- no protein function and

disease relevance

Protein Function:- purification and structure

determination- ~100,000 proteins in human- 75% no known cellular functions

Small Molecules:- modulate biological functions of proteins

ControlBiologicalFunctions

Drug Drug DiscoveryDiscovery

첨단화학의 이해

proteinnormalsignal activateactivate

protein functionprotein function

deactivatedeactivateprotein functionprotein function

falsesignal

Protein Function (Drug Action)

첨단화학의 이해

N

HNN

N

NN

O

O

Viagra(treatment of impotence)

N

NCO2Et

Cl

Claritin(antihistamine,i.e. antiallergic)

NH

N

O

OH

S NHO

HO

H

H

Viracept(treatment of AIDS)

NH

O

OO

F

Paxil(psychotherapeutic)

F3C O NH

Prozac(antidepressant)

NHS

O

HO2C

Captopril(treatment of hypertension)

N

N N

N

O

H2N

OHO

Acyclovir(antiviral)

N

N

Cl

O

Valium(tranquilizer)

HN OPt

O O

H2N NH2

Carboplatin(treatment of ovarian cancer)

O

O

NMe2

NH2

Novocain

(local anesthetic)

Selected Medications of 20th CenturyNH2

ClCl

Zoloft(psychotherapeutic)

N

HN

S NMeO

O

OMe

Prilosec(antispasmodic)

OS

HN

N

NO2

HN

Zantac(treatment of ulcer)

N

HN

SNH

NH

NCN

Tagamet(treatment of ulcer)

첨단화학의 이해

HO

H

OH

H H

O

H

OH

H H

H

17-ethynylstradiol norethindrone

(the "Pill"; contraceptive)

O

O

OHHO OMe

O

O

O

HON

OMe

OH

Clarithromycin(antibacterial)

N

S

HOO

O

H H

CO2H

NH2

Ampicillin(antibiotic)

NO

H

CO2H

OH

Clavulanic acid(β-lactamase inhibitor)

Augmentin(antibiotic)

Selected Medications of 20th Century

O

HO

RO

N

R= H MorphineR= Me Cocaine

(pain killer)

OO

O

OH

OH

R H

R= HR=Me

MevacorZocor

(treatment of high cholesterol)

첨단화학의 이해Target-Oriented Organic Synthesis

Known active sitesof target proteins

Design and synthesisof target molecules biological effects

첨단화학의 이해

정상

이상

Diversity-Oriented Organic Synthesis

Library of diverse small molecules

unknown proteins

첨단화학의 이해

Combinatorial ChemistryCombinatorial Chemistry

첨단화학의 이해

44 = 256개tetramer

Combinatorial Library

4 개의 monomer

••••

Nn Combinations

첨단화학의 이해

resin +monomer

shakeresin

cleavage

wash

Solid Phase Synthesis의기본원리

wash

첨단화학의 이해

Solid-Phase Synthesis of Peptides

polymerbead

amino acid

cleave

In 1960s, Bruce Merrifield: peptide synthesis from amino acids

peptide

첨단화학의 이해

Solid Phase Library Synthesis

• polymer supported synthesis: easy purification• fast generation of diverse library of molecules in few steps• limited reactions compared to solution reactions

Split-Mix (split-pool) synthesisParallel synthesis

첨단화학의 이해Split-Mix Process

Mix-SplitCouple

Mix-SplitCouple

33= 27tag each bead!

첨단화학의 이해

Parallel synthesis

- synthesis of small number of focused library

- no tagging beads!

첨단화학의 이해

Solid Phase Library

203 = 8000 tripeptides

20 amino acids

202 = 400 dipeptides

204 = 160,000 tetrapeptides

In 1991s, Houghten & Lam: synthesis of a huge peptide library

peptideDNA: fully automatic (solution)

Solid-phase synthesis

ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid phase synthesis

carbohydrate

small molecule (drug-like)

첨단화학의 이해

2,180,106 compounds

Combination of Chemical Building Blocks

첨단화학의 이해Virtual Library

virtual library: computer simulated fitting of virtual molecules with the active site of the target enzyme

Novel compounds that bind to enzymes or receptors can be discovered by finding two fragments that bind and then synthetically combining

첨단화학의 이해

Applications of Combinatorial Chemistry

Pharmaceutical industry: rapid synthesis of a huge number of drug-like molecules

Material science: new approach for the discovery of new materials

Catalyst discovery: fast discovery of new catalysts

Chemical biology: diversity-oriented synthesis of small organic molecules

첨단화학의 이해

Supramolecular ChemistrySupramolecular Chemistry

첨단화학의 이해

1. Molecular chemistry- Covalent bond

H2N NH2

O

150 years ago

urea

palytoxin

첨단화학의 이해

초분자 화학

2. Supramolecular chemistry- Chemistry beyond moleculesAssembly of molecules – Molecular recognition

1987 노벨화학상: 초분자화학Charles Pedersen, Jean-Marie Lehn, and Donald J. Cram

Non-covalent bonds:- electrostatic forces- hydrogen bonds- van der Waals interactions- dipole interactions- hydrophobic interactions, etc)

첨단화학의 이해 DNA and Hydrogen Bonds

N

N

NH2

R

N

NN

N

O

R

H

NH2 N

N

N

N

O

O

H

R

NH2

OR

thymine adenine

guanine cytosine

O Base

O

POO

O

첨단화학의 이해DNA and Hydrogen Bonds

NN

N

N

O

RH

NN

N

N

O RH

H

HH

NN

N

N

N

RN

NN

O

O RH

H

HH

H

Which pair forms stronger hydrogen bonds? And Why?

-

+

+

+

-

-

+

-

+

-

+

-

첨단화학의 이해DNA and Hydrogen Bonds

3.9x108 M-1 3.6x106 M-1 3.3x104 M-1 3.3x104 M-1 3.1x102M-13.6x106 M-1

++++

----

+++-

---+

++-+

--+-

+--+

-++-

+-+-

-+-+

++--

--++

N

NN

HR

OH

N

O

H

N

NN

HR

OH

N

O

H

2

N

N N

HR

OH

N

O

H

첨단화학의 이해

New Materials Based on Hydrogen Bonds

N

N N

HR

OH

N

O

H

N

NN

HR

OH

N

O

H

N

N N

HR

OH

N

O

H N

NN

HR

OH

N

O

H

N

N N

HR

OH

N

O

HN

NN

HR

OH

N

O

H

N

N N

HR

OH

N

O

HN

NN

HR

OH

N

O

H

N

N N

HR

OH

N

O

H

n

첨단화학의 이해Crown Ethers

18-crown-6 15-crown-5

OO O

OO O

O

O O

OO

Na+K+

O

O

O

O

N

O

N

O

O OOOO O

K+K+

Cryptand

- 11 kcal/ mol - 18 kcal/ mol

Crown ether

NO

O

N

ON

CH3

CH3

H3C

N+

H

H HR

첨단화학의 이해

W.C. Still D.J. Cram

Preorganized Ionophores

OO

O

OOO

K+

OO

OO O

OH H

H HK+

OO

O

OOO

OOMe

O

OOOMe

MeMe MeMe

Preorganization: both binding affinity and selectivity are considerably increased

첨단화학의 이해Anion Recognition

첨단화학의 이해Anion Recognition

첨단화학의 이해Chemosensors

Signals:- fluorescence- color- electric signal...

첨단화학의 이해Chemosensors

ONH

N

CH3H3CN N

OHN

Hg(OAc)2

ONH

NH

CH3H3CN NH

OS

NH

Hg(ClO4)2, CH3CN(98%)

H2O-MeOH(4 : 1)

1 only Hg2+ Ag+ Cu2+ Cd2+ Pb2+ Zn2+

첨단화학의 이해

Carcerand

O

O

+ CO2

첨단화학의 이해

Molecular MachineMolecular Machine

첨단화학의 이해생체 분자기계

ATP Synthase

Bacterial Flagellar Motor

Linear movement - muscle(myosin moving along an actin filament)

첨단화학의 이해 Interlocked Molecules

RotaxaneRota (wheel) + axis (axle)

CatenaneCatena (chain)

첨단화학의 이해

분자 셔틀

첨단화학의 이해

A catenane-based switching device for electric circuits.

분자 셔틀

첨단화학의 이해

Catenane-based molecular rotor. A unidirectional rotation of the small rings along the large ring is achieved by their sequential complexationand decomplexation with four station parts A-D on exposure to light, heat, and chemical stimuli.

분자 셔틀

첨단화학의 이해분자 근육

첨단화학의 이해분자 엘리베이터

첨단화학의 이해분자 가위

첨단화학의 이해분자 모터

Chiral molecular motor composed of a tetrasubstituted alkene. Photoinduced and thermal-induced unidirectional rotation.

첨단화학의 이해분자태양전지