Transcript 항암제 [ Anticancer agent ]

항암제 [ Anticancer agent ]
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Contents
1. 암의 정의 및 발암 기전
2. 항암제의 분류
3. 항암제의 구조와 작용 기전
4. 기타 항암제
1. 암의 정의 및 발암기전
 종양(tumor)의 정의
생체세포의 일부가 비정상적으로 증식, 신생물(neoplasm)
 종양의 분류
① 양성종양 : 발육이 완만, 생명에 영향을 미치지 않음
② 악성종양 : 침윤성 또는 전이성이 있어 위험
1. 암의 정의 및 발암기전
Cellular Transformation
Normal cells
정상세포
Neoplastic (cancer) cells
암세포
Carcinogenesis
Carcinogens: 발암인자
• 물리적: 방사선, 자외선 등
• 화학적: 발암화학물질
• 생물적: 발암 바이러스
대사길항제
Intercalator, DNA 절단제
유사분열 저해제
2. 항암제의 기전과 분류
1.
알킬화제
(alkylating agents)
2.
대사길항제
(antimetabolites)
3.
Antibiotics
4.
Topoisomerase Inhibitor
5.
6.
유사분열 저해제
(antimitotic agents)
호르몬제
2. 항암제의 구조와 분류
1) phase non-specific
Akylating agent
2) S phase specific
Enzymes
3) M phase specific
vinca alkaloids
3. Structure & Mechanism
1. 알킬화제
nitrogen mustard
(mechloethamine,
chlorambucil)
Aziridine
(thiotepa,
trimethylenemelamine)
methanesulfonate
Cl
Cl
H3C N
HOOC (H2C)3
N
Cl
Cl
S
N
N P N
N
N
N
N
N
N
OSO2CH3
H3CO2SO
Busulfan
백금착체
(cisplatin, carboplatin,
tetraplatin)
O
H2N
Cl
Pt
H2N
Cl
Cisplatin
H2N
O
Pt
H2N
O
O
Carboplatin
H Cl
N
Cl
Pt
N Cl Cl
H
Tetraplatin
Mechanism of Nitrogen mustard
Nitrogen mustard
2차 세계 대전시 사용
면역기능 약화
highly electrophilic
: Guanine의 nucleophiles인 7-nitrogen 반응
-> 복제 및 전사 불능
Cross linking
이 일어남
Aziridines
S
Thio-TEPA
( Thiotepa )
N P N
N
Triethylenemelamine
( TEM )
N
N
N
N
N
N
O
Diaziquone
(AZQ)
N
NHCOOEt
EtOOCHN
N
O
O
Mitomycin C
(Mutamycin)
OCONH2
H2N
OMe
N
H3C
O
NH
Cross linking by Mitomycin C
Platinum compounds
O
H2N
Cl
Pt
H2N
Cl
Cisplatin
H2N
H Cl
N
Cl
Pt
N Cl Cl
H
O
Pt
H2N
O
O
Carboplatin
Tetraplatin
Guanine group에 붙어서
DNA 복제 차단
Methanesulfonate
O
OSO2CH3
H3CO2SO
Guanine
OSO2CH3
N
HN
H2N
Busulfan
N
DNA
N
Monoalkylated adduct
+
O
O
N
HN
H2N
N
N
N
N
DNA DNA
Dialkylated adduct
NH
N
NH2
3. Structure & Mechanism
2. 대사 길항제
엽산 길항제
(methotrexate)
SH
Purine 길항제
SH
N
N
N
N
H
H 2N
6-Mercaptopurine
Pyrimidine 길항제
(5-Fluorouracil)
N
N
H
6-Thioguanine
O
F
HN
O
N
N
N
H
Methotrexate
Thymidine sysnthesis
Methotrexate
Thymidine sysnthesis
Methotrexate
Folic acid
Methotrexate
SAR of DHF reductase
Methotrexate
effect
Purine antogonist
Pyrimidine antogonist
5-FU(fluoroUracil)
thymidylate synthase
5-FU
dTMP
dUMP
DNA
methylene-THF
DHF
dihydrofolate
reductase
MTRX
serine hydroxymethyl transferase
THF
5-FU mechanism
O
O
F
HN
O
5-phosphoribosyl1-pyrophosphate
HN
O
N
H
O
F
ATP
N
O
Ribose-P
5-fluorouridine
monophosphate, FUMP
F
HN
N
Ribose-PP
5-fluorouridine
diphosphate, FUDP
ribonucleotide
reductase
O
O
F
HN
O
O
N
F
HN
O
OH
N
dRibose-P
E-SH
F
HN
O
N
H
S-enzy me
dRibose-P
N
dRibose-PP
5-fluorodeoxyuridine
diphosphate, FdUDP
dRibose-P
5-fluorodeoxyuridine
monophosphate, FdUMP
O
F
HN
methylene
THF
O
HN
O
N
CH2-THF
F
H
S-enzy me
dRibose-P
ternary complex
3. Antibiotics
Amsacrine
Actinomycin
O
OH
O
R1
R2
R3
Doxorubicin
CH3O
OH
H
R4
OH
Daunorubicin
CH3O
H
H
OH
Idarubicin
H
H
H
OH
Epirubicin
CH3O
OH
OH
H
R2
OH
Anthracycline
R1
O
OH O
H3C
O
R3
NH
R4 2
Amsacrine
Intercalating agent
: 화합물들이 DNA 염기쌍에 끼어 들어감
2-4개의 평평한 환을 함유
+전하를 띄는 질소가 고리 내 또는 측쇄에 존재
Intercalating agent
Anthracycline D
Mitoxantrone
Anthracycline
해리상수와 항암활성이 상관관계가 있음
펩타이드 치환기들은 minor groove에 존재함
Sar
Sar
l-Me-Val
l-Me-Val l-Pro
d-Val
O
O
l-Thr
l-Thr
NH
HN
O
O
구아닌의 2-아미노기와 H-결합 형성
구아닌의 2-아미노기와 H-결합 형성
N
NH2
l-Pro
O
CH3
O
CH3
Topoisomerase Inhibitors:
1.Topo II inhibitors
• Anthracyclines
•
•
•
Doxorubicin, epirubicin, idarubicin
Epidophophyllotoxins
Etoposide, Teniposide
2. Topo I inhibitors
•
Irinotecan, Topotecan
Topoisomerase II
H3 C
O
O
O
HO
O
OH
O
OH
O
C
O
CH2OH
OH
O
CH3O
O
O
O
O
O
CH3
CH3O
OCH3
NH3
OH
OH
Dox orubicin
(Adria my cin)
Etopo side
(VP-16 )
NHSO2CH3
OH
O
HN(CH2) 2NH(CH2) 2OH
CH3O
NH
OH
O
NH(CH2) 2NH(CH2) 2OH
N
Mito x antro ne
Ams acrine
(m-AMSA)
Fig. (5). Molecular structures of topo II targeted anticancer drugs.
Some of the most widely used anticancer drugs such as etoposide and
doxorubicin have been shown to target topo II
Topoisomerase I & II
anthracycline 계
Topoisomerase II 안정화
→ DNA strand 파괴를 유발 시킴
→ DNA 손상은 apoptosis를 유도시킴
Topoisomerase I
H
CH 3
NH 2
N
CH3
CH2
HO
A
B
C
N
N
A
O
C
N
N
D
E
C 2H 5
OH
A
O
B
D
C 2H 5
OH
O
C
N
C
O
D
E
O
O
C 2H 5
OH
O
O
Top otecan
9 -Amin o Camp to th ecin
O
N
N
E
O
Camptoth ecin
N
B
CH2CH3
CH 2CH3
HO
O
A
B
C
N
N
O
D
Irino tecan (CPT 1 1)
E
C 2H 5
OH
es teras e
A
B
C
N
N
D
SN-3 8
O
E
C 2H 5
OH
O
O
O
O
Fig. (4). Molecular structures of camptothecin and derivatives. The
activity of camptothecin against topo I requires an intact lactone ring.
The carboxylate analog is inactive. Irintotecan is a pro-drug that
requires hydrolysis to SN-38 for activity. Irinotecan is active against
colorectal cancer and topotecan shows activity against ovarian cancer.
Nine-amino camptothecin has not yet been shown to have significant
activity against human malignancies
5. Antimiotic agent (유사분열 저해제)
Microtubule
Tubuline subunit으로 구성
Mitosis의 중요 역할
물리적으로 cell 성분을 cell
끝 쪽으로 옮김
Inhibitor
:Vinca alkaloids
5. Antimiotic agent (유사분열 저해제)
OR
OH
O OMe N
O
O
CH2CH3
N
H
H
O
N
O
OH
MeO
N
R
Vincristine R = -CHO O
Vinblastine R = -CH3
H
CH2CH3
MeO
OCOCH3
OMe
OMe
OMe
R = H Phodophyllotoxin
H C
R= 3
MeO
NHCOCH3
O
O
HO
O
OH
Etoposide, VP-16-213
H3C
OMe
O
Colchicine
6. Hormone 류
O
H3COCO
H3C
OH
CH3
CH3
R
CH3
HO
H
H
O
CH3
O
O
O
3' 2' O
H H H
C N C C C O
O
Taxol R =
OH
3' 2' O
H H H
Taxotere R = H3C C O C N C C C O
CH3
OH
CH3
O
Glivec
Glivec
EGFR Inhibitor