BO GIAO DUG VA DAO TAO
TRU'O'NG
OAI
HOC TONG HOP HA NOI
PGS PTS
PHAM TRUONG
THI THO
NGHIEN
CLTU
BAN TONG
HCfP
DjNH HU-QNG
CAC
DAN
XUAT
EUGENOL CO TAC DUNG
KHANG NAM C. ALBICANS
LUAN
AN TIEN
St
KHOA HOC HOA HOC
HA NOI
1994
MUC LUC
Phan mot
Trang
Chirang
ma dau 1
-
Gidi
thieu

Mdi
hen quan dinh
luong
"Cau
true
hoa hoc va 14
tac dung sinh hgc" (QSAR)
'
.
0-5 Nhung md hinh toan hpc nghien cuu
vtin
de QSAR 16
a-
Phuong
phap nhan dang, phuong phap phan tich cau
true
con 16
b-
Giai phap ve cac Juong
til thdng
ke 17
c-
L/ng
dung phan tich nhan td de tim hieu quan he
c^u
true
- tac dung
18
d-
Cac phuong phap ban

1-2 Muc dich cua cdng trinh 34
1-3 Cac phuong phap nghien cuu 34
Phan hai
NHUNG KET QUA NGHIEN CUU
Cliitrang
2: Mot so
ichdo
sat ma dau
2-1 Nghien cuu thanh phan hda hpc tinh dau huong nhu
38
trang
(Ocimum gratissimum
L., Labiatae) Viet Nam 40
2-2 Khao sat dinh tinh tac dung khang khuan, khang
nSm
40
cua tinh dau huong nhu va eugenol.
2-3 Nghien cuu quy trinh tdi uu tach eugenol tu tinh dau huong nhu.
42
2-4 Nhung nghien cuu md dau chuan bi cho viec ban tong hop
45
cac din xuat eugenol.
2-5 Nghien cuu su phan bd dien tich cua nguyen tu trong phan 49
tu
eugenol,
isoeugenol
vave gidn
do phan
tir
cua chung

true VH (1-hydroxy
- 2-metoxy -
4<2',
3'
dibrompiropyl)
-6-brom-benzen) 59
3-2-1-5 Cong hop hydrohalogenua 59
* Xac dinh cau
true
VIII (Bis (1-hydroxy - 2-metoxy - 62
4-propenyl-benzen)
3-2-2 Nhirng phan
irng
iam thay doi nhom - OH 64
3-2-2-1 Tao este voi axil ciorua
'
a- Este hoa eugenol vo'i benzoyl ciorua trong moi tnrang kiem
^
b-
Este hoa isoeugenol
vd*i
benzoyl ciorua 65
c-Este hoa eugenol
vol
p-clobenzoyl
ciorua 65
3-2-2-2 Tao este
vdi
p-toluyl
sunfoclorua

c£u true
XX
81
(1-p-ciobenzoyl
oxy - 2-metoxy -
4-alyl
-
6-aitro-benzen)
•t
3-3 Tinh mat dp dien
tCt
hda tri tren cac nguyen tu C va O 88
theo
phuung
phap
CNDO/2'va
ve gian do phan tu cac
din xu^t
eugenol (theo chuong trinh Alchemy)
3-4 Ket qua va thao luan
96
Chirang 4: Xac dinh
dinii licang
tac dung
Iciidng
nam C.albicans cua
18 dan xuat eugenol theo mo
iiinh
toan
iioc

dan xuat cd tac dung cao hon.
115
Chirang
5:
Xac dinh dinh
lirang
moi lien quan cdu
true
- tac dung
cila
cdc dan xuat eugenol theo mo
liinli Corwin
Hansch
5-1 Gidi thieu them ve md hinh Hansch
117
121
122
5-2 Cac thdng sd hda ly
^ 19
5-2-1
Hang
sd cam ung nhdm
th6 a ^-^9
5-2-2 Hang sd hieu ung lap the Es
5-2-3
Hangsd the'ky nude (Ig
P)
5-2-4 Hang sd ky
nude
bp phan hay hang sd phan ra f 124

6-2-2 Ket qua nghien cuu theo md hinh Free - Wilson 138
6-2-3 Ban tong hpp
din
xuit brdm eugenol (m) va dan xuit
este eua toluyl
sulfoeiorua
vdi brdm isoeugenol (M) 139
6-2-4 Ket qua thu tac dung khang nam C.albicans eua hai din
xuat (m) va (M)
142
6-2-5 Thao luan cac
k6t
qua 142
6-3
Ket
luan 142
Chuang
7: Thao luan ve kha nang
mo*
rong hai mo
hinh
nghien
cii'u
cua
Free-Wilson va Hansch 146
7-1
Nhan xet ve hai mo hinh Free-Wilson va Hansch
^43
7-2
Gid-i

7-3-5 De xuat them ve kha nang md' rpng
phirang
phap Free-Wilson 156
7-4 Ket luan 159
Phan ket luan: Nhirng ket luan. Nhung dong gop cua luan an 160
Phan thurc nghiem 162
Phan cdc tdi lieu tham
klido
Phan phu luc
169
189
Phan mot
CHl/QNG MQOAU
1.
Gi6>i
thieu luan an
Ten de tai: "Nghien
cmi
ban tong
hgp
dlnh
hud'ng
cac dan xuat eugenol co tac
dung khang nam Candida
albicans".
Luan an gom 190 trang va 40 trang phu luc, dan 185 tai lieu tham khao va
du-gc
chia
lam
7 chirang,

hmi
tac gia
ciia
Uy ban Phat minh sang che Bungaria (No. 43770 va
No.
43771), va da bao eao tai mot so hoi thao quoc gia va quoc te
nhir:
Hoi nghi
quoc.
te ve tinh dau va chat tham cua Bungaria (Vacna, 17-19/10/1985), Hoi nghi Hoa
hpc'
quoc gia lan
thu*
nhat cua Bungaria (Sophia, 26-28/11/1985), Hpi
nghj
quoc te ve tinh
dau va chat tham lan
thu*
2
ciia
Malaixia Kuala lampur (3-5/12/1990), Hpi nghi quoc
te ve
hirang
lieu my pham Chau A lan
thu*
nhat (Singapore, 22-24/10/1991), Hpi nghi
quoc te ve tinh dau va chat tham lan thu 3 Malaixia (Langkawi Island kedah), Hpi
nght "Cay nhiet
ddi
va ung dung" do UNESCO to

nud-c
ta, bang con du'o'ng nao de cd the tong hgp
du-gc
cac dan xuat
ciia
eugenol c6 tac dung khang nam C. albicans (mpt loai nam dac
tru'ng cua benh ngoai da va benh phu
nu)
cd hieu qua
ca*
de cd the
su*
dujig
trong
nganh y
dugc
hoac trong nganh my pham. Ket qua thu dugc co the dong gdp vao viec
nang cao hieu qua
su
dung tinh dau
huang
nhu, mpt nguon tai nguyen con ehua dugc
tan dung.
Vdi
muc tieu do, chung tdi da tien hanh thay doi cau
triic
eugenol bang each thay
doi cac nhdm chuc, roi nhd cac md hinh toan hpc khao sat moi lien quan giua su thay
doi cau
true

tinh
mdi me
ciia
cdng trinh.
Tinh Icinh
te vd
klioa
hoc
ciia
cdng trinh the hien d cho vdi mpt so
lugng
ft nhat
cac dan xuat can tong hgp (theo mpt quy hoach da chpn va la dai dien cho mpt sd
lugng
Idn
gap nhieu lan cac dan xuat le ra can phai dieu che de thu nghiem theo cac
phuang phap truyen thong), va viec su dung cac phuang phap
tinh
toan lugng tu,
khong lugng tu, xu ly so lieu vdi phuang tien may tinh dien tu v.v., cuoi cung da tim
ra dugc dan xuat cd tac dung tot nhat theo yeu cau vdi con dudng ngan nhat.
Ngoai ra, ve mat ly thuyet luan an cung da de xuat va thao luan kha nang md
rpng viec su dung hai md hinh Free-Wilson va Hansch nham tim vai trd tugng tac
ciia
cac nhdm the trong phan tu, dieu nay chua dugc hai md hinh tren nhac den.
Chung tdi da lien he hai md hinh Free-Wilson va Hansch vdi ly thuyet quy noach
thi
nghiem, phan
tich
so sanh ban chat cac tham so vao va tham so ra, phan

nude
ta van de nay cung rat mdi.
Diem ca ban
ciia
luan an nay la su tim kiem nhung phuang phap mdi, khoa hpc
va kinh te, nham giai quyet van de ban tong hgp cac dan xuat cd tac dung sinh hpc tu
nguon goc thien nhien mpt
each
cd dinh hudng.
Chiing tdi muon coi do la diem ddng gdp mdi va ca ban
ciia
luan an. Can noi
them rang phuang phap ban tong hgp dinh hudng nay khdng phai chi dung lai d
nhung ket qua cu the
ciia
luan an, ma con cd the lam tien de cho nhung nghien
cii'u
tiep theo, rat phong
phii
va da dang.
PHAN TONG QUAN
0-1.
Cac dan xuat eugenol
duo'c
biet den nay
Eugenol, C10H12O2 .
Phan tli' lugng M
=
164.
Eugenol cd 3 nhdm chuc ta

chua bi the (vj tri so 3, 5 va 6). Nhin chung cac dan xuat deu xuat phat tu su thay
doi cac nhdm d vi tri 1, vi
tri
2 va vi
tri
4 [65, 67, 68, 69, 146], hoac dinh cac nhdm the
vao
vi tri
5 va 6. Cho den nay chua ed mpt tai lieu nao noi den viec dua nhdm the vao
vi
tri
3, cd the do vi
tri
nay bi can trd khdng gian bdi cac nhdm the metoxy va
alyl."
D6i
vdi cac vi
tri
5 va 6 thi nam 1933 David E, Levin va Alexander Lowy da dua cac
nhdm nitrobenzylamin va
nitrophenylamin
vao vi
tri
6 d vong tham
ciia
phan tu
dihydro eugenol [21], nam 1915 Brady Dann [11] da dua nhdm nitro vao vi trf 5
ciia
vong tham d vanilin, nam 1925 Menke B. [64] va nam 1930 Torrey Clarke [94] da dua
dugc nhdm brdm vao vi tri 5

eugenol. Tu nam 1904 den nam 1979 so cac dan xuat eugenol dugc biet da len den 80
(xem phan phu luc [165 - 183]). Nhung dan xuat dugc tao nen do cd su thay doi nhdm
chuc d vj
tri
1,
thi
du thdng qua cac phan ung este hda, thudng cd mui tham dac trung.
Mpt so chat da cd mat d thi trudng va dugc su dung vao nganh huang lieu my pham
nhu axetyleugenol, axetylisoeugenol cd miii tham hanh nhan [88], einamyl eugenol,
eugenol cinamate deu cd nhung
miii
tham dac trung rat ben. Viec chuyen nhdm alyl
d vi
tri
4 thanh nhdm -CHO da tao thanh
chSl vanihn
quen thuoc. Thdng qua su dong
phan hda eugenol da thanh isoeugenol, phan ung nay da cd nhieu tien bd ve mat ky
thuat. Trudc day su dong phan hda nay dugc thue hien trong mdi trudng kiem
d$c
cd
dung mdi, sau nay qua trinh dong phan hda vdi kiem nong chay da cho hieu suat cao
hem.
Nhd cac
Id
vi sdng Andre Loupy va Le Ngpc Thach da dong phan hda eugenol
thanh isoeugenol mpt each hieu qua va nhanh chdng [2].
M6t
so dan xuat eugenol cd tac dung sinh hpc nhung khdng dac hieu, nhu san
pham the nitro vao vi trf 5

Kaempgen
Dieter
ndi den kha nang chua benh AIDE
ciia
hon hgp eugenol va
isoeugenol [50]. Dd la nhung tich chat quy gia ma chiing ta cd the khai thac. Tuy nhien
<iho
den nay chua cd nhieu cac dan xuat dugc dieu che nham uc che cac nam benh.
Nhin chung, nhung dan xuat eugenol dugc ban tong hgp cho den nay vdi muc
dich
con
rdl
rac chua dinh hudng.
0-2, Van de nam benh
6-
cac
nu'd'c
co
khi
hau nong am va
6*
Viet Nam
A - Benh ngoai da {da lieu)
Phan Idn cac benh ngoai da gay ra bdi eac dang nam ky sinh
thue
vat, cac loai
nam nay thich nghi va phat trien tren cac cho san
ciia
da.
Cac benh ngoai da d rgc gay ra bdi cac loai vi trung va nam khac nhau dugc gpi

nghien
cuu ky nam 1973 tai phong thi nghiem
thii
y Sai Gdn.
(y
cac nude Ddng Au nhu Bungaria nhieu loai nam benh ngoai da cung phat
trien [153, 154, 155]. Loai nam pho bien nhat d Bungaria la Epidermaphyton
floscosum
[152].
Nam 1970 bac si I. Gruzozov [156] da phan lap tu 100 benh nhan ed
cac loai nam nhu sau:
Trichophyto rubrum 57%, Candida albicans 32%, Trichophyton interdigitel 6%
va Trichophyton mentagrophytes 5% [159, 160].
B.
Nhitng
nhom chat khdng sinh chinh [183]
1.
De nghien cuu cau
true
va ca che tac dung
ciia
eac chat khang sinh, ngudi ta da
phai khao sat ti mi tu cau tnic
ciia
vach te bao vi khuan (vi khuan gam am, vi khuan
gam duang) den cau triic
ciia
vach
ciia
cac loai nam benh (thanh phan hda hpc va kha

Tao
xanh:
4-
Chat khang sinh ban chat nucleotidic hoac cd hp hang vdi cac baza puric, hoac
thupe loai nucleozid, hoac tao thanh bdi
sy
lien hgp
ciia
nucleozid vdi eac
chat khac
5-
Chat khang sinh vdi nhan tham ngung ket
6- Chat khang sinh vdi di vong nita
7-
Chat khang sinh chua cac dan xuat oxy hda
ciia
nita
8- Chat khang sinh chua cac dan xuat
ciia
glutarimid
9- Chat khang sinh vdi di vong oxi
10-
Chat khang sinh vdi phan tu lugng nhd, dan xuat tu cyclopentan hoac
cyclohexan
11-
Chat khang sinh chua do
12-
Chat khang sinh chua luu huynh
13-
Chat khang sinh chua brom

da mo ta
83
198
10
3
28
1
da sic dung
0
24
1
2
3
3
dugc tao ra bdi mpt ehuoi eac dan vi isopren nhu:
a- Moenocinol:
CH2OH
b- Fumagilline: cd cdng thue (b), dugc dung cho ngudi de chong lai amfp
rudt,
hai dpc (LD50 800 mg/kg - theo dudng dudi da chupt)
CH3
\CO-(CH=CH)^-COOH
(b)
c- Trichodermine (c): la mpt khang nam sinh chong nam va la dai dien dan gian
nhat cua ca nhdm khang sinh secquiterpen - trong so nay cd the ke tdi
crotocine
(d)
chiet suat tu caphalosporium crotocinigenum va rocridine A (e) chiet suat tu
myrothecium roridum.
CK-CHOH

(h)
H
O
CH3O
COOH
CO-CH3 (g)
(i)
10
Cephalosporine manh han axit nelvonic 5 lan. Con axit fusidic lai manh han
cephalosporine
Pi
tdi 10 lan. Cae chat khang sinh nay cd tac dung tdi khuan gam
duang d nong dp tu
0,02//g/ml
-
0,2/^g/ml,
ddi vdi khuan
M.
tuberculosis thi ndng dp
1
/ig/ml
(chiing ft dpc LD50 200 mg/kg dudng ven chupt).
e- Viridine (i): Viridine la chat chong nam, chiet suat tu Gliodadium virens va
Trichoderma viride. Viridine cd tac dung chdng nam tot, song rat dpc ddi vdi ngudi
(LD50 < 5 mg/kg) nhung cd the diing cho cac benh thue vat.
Nhirng chat co
iac
dung khang nam C. albicans
Cac tac gia My Erie J. Lien va Corwin Hansch [24] khi nghien cuu
tinh

thii
vi song thue ra cho den
nay van de nay van cdn chua giai quyet tudng tan, vi vay trong
luan
an nay tac gia
khdng cd tham vpng di sau vao ca che tac dung
ciia
che pham thuoc len nam ma chi
11
nghien
cii'u
vai trd cac nhdm chuc va vi trf cac nhdm the trong phan tu eugenol len
tac dung khang nam C.albicans, nham tim ra mot che pham ed hieu qua tac dung cao
cd the su dung vao lam sang,
0.3 . Van de tong
ho-p
noi chung va
su*
tong
ho'p
co dinh
hirdng
Vao nhung nam cuoi
ciia
the ky 19, ly thuyet cau tao hda hpc sang lap bdi A. M.
Butlerov
nam 1861 la mpt cudc
each
mang trong hda hpc,
ciing

Dii
vay, cho den thdi ky nay cd
the ndi rang, dudng hudng tong hgp van mang nhieu
tinh
chat ngau nhien, may
riii
va
'
rdi rac.
Nhung nam 40
ciia
the ky 20 da md ra nhung
bude
tien mdi trong hda hpc huu
ca, bat dau bang nhung thanh tuu ve hda huu ca ly thuyet va hda ly thuyet, nhu ve ca
che phan ung, ve cac tieu phan trung gian khdng ben vung (Caebocation, Cacbanion,
cac goc, eac arin ), ve phan tfch cau hinh, ve hda lugng tu thi viec tong hgp huu
ca da ed nhieu thanh cdng mdi.
Den nam 1956 nha khoa hpc dugc giai thudng Noben R. B. Woodward da nhan
manh den vai trd
eiia
quy hoach cd y thue trong
linh
vuc tong hgp hu-u ca bdi le
thuoc thdng thudng can tong hgp khoang 5000 - 7000 chat mdi, mdi cd dugc mpt chat
12
dung
dupfc
vao dieu tri, do do con ngudi
ludn

la
nhiing tong
hap da trd thanh khudn
mSu,
cdn tong
hgrp
"phi
ly"
dupfc hinh thanh nhd cd su sang
tao trong suy
nghi
cua nha
thi
nghiem va quy tac chung de quy hoach tong hpfp
la
bat dau tuf phan
tich
cau tao phan tuf
cha't
c^n
tong hpfp, cd
nghia la
chpn phan tu can
tong hpfp, rdi xem xet cac con dudng hoac each thiic de tong hpfp dupfc chat dd. Tu dd
din den viec thanh
Iap(md
hinh) bieu dd tong hpfp .( Md
hinh
) bieu dd tong hpfp nay
cd cac nhanh - van de

che
phim
mdi vSn cdn nhieu han che. Mai den sau nam 1960 khi ma cac
nganh khoa hpc phat trien mpt budc dai, dac biet
la
cac nganh dien tu, tin hpc,va su
su£t
hien nhung mdn khoa hpc
lien
nganh mdi nhu khoa hpc ve" mdi
lien
quan
gifia
cau tnic hoa hpc va tac dung sinh vat hpc" [30,32] thi viec tong hpfp hoa hoc da mang
mpt mau sac mdi. Dd la viec tong hpfp hoa hpc cd dinh hudng. Su tong hpfp cd dinh
hudng
la sa
tong hop chat mdi theo mpt chien
luac
tim
ki6m,
theo mpt muc tieu de ra
trudc,
tac dung da dinh sin, ke hoach cu the de tien hanh. Ngudi nghien cuu biet
rd can phai thay ddi cau tnic nhu the nao, thay doi nhdm the nao, d vi tri
nao va can tong hpfp bao nhieu din chat mdi de cd the tim ra duac mot
chat mdi cd tac dung cao hon ca theo tac dung da dinh trudc,
ching
nhirn*^
xac dinh duac chat cd tac dung tot nhat ma cdn cd the du doan duac chat

nfmg
thiet lap mdi lien quan giua ca
' true
hoa hpc va tac
dung sinh hoc da
dupe
de cap gan 100 nam trudc, khi ma ngudi ta phat hien
ra rang luc tac dung gay me
eiia
eac chat thuoc giam cung vdi su tang len dp
hoa tan
eiia
chung d trong
nude.
It
ifiu
sau, mdi lien quan
giOa
kha nang gay
me va su phan bo eac chat trong he thdng nude
-
lipid.cung
dupe
phat hien.
Tiep sau dd, toan bd day cae thdng sd hda ly cua cac chat cd lien quan den tac
dung gay me va dpc tinh tang len cung da dupe thiet lap va dupe mo ta bdi
H.B.
JIasapeB
[137].
Mac du cdn han che va cdn mang tinh chat djnh tinh, da so nhung phat

= JS/'I trong ddi=
l,2,3, ,n.
(i)
2-
Ton tai mdi quan he giua cau
true
hpp chat va tac dung sinh hpc
ciia
14
no,
tiic la
ton tai mpt ham Fy(AySy) nao dd lien quan tac dung A
ciia
chit Y vdi eiu
triie
Sy, hoac la vdi dac trung rieng re
ciia
cau true dd -
Fy(S/,Ay).
3-
Neu dang cua ham so F(S,A) dupe thiet lap thi ham nay cd the dupe
ngoai suy ra eho diy hpp chat
Yi,
Y2,Y3,
cd eiu
triie
gidng nhau chi
khac nhau bdi cac nhdm the'
Xi,
X2, X3 hoac la bdi vi tri eac nhdm

lupng
[A]. Dai
lupng
[A] thudng
dupe
xac
dinh bdi cac thi nghiem sinh hpc.
N6u
cac dac trung hoa ly
ciia
cae
chit phan anh su bien ddi eiu triic eua chiing qua day cac thdng sd
ciia
chiing dupe
thue
hien thi quan he Fy (Sy,Ay) dupe thiet lap. Rd
rang rang nhiem vu
phiic
tap nhit de
thi6t
lap quan he ndi tren la
viec tham sd hoa [A].
[A]
la
sd do
Jinh
lupng eua tac dung sinh hpc. bieu thi bang ndng dp, va
[BR] la sd do dinh lupng hieu
ling
sinh hpc bieu thi bdi cae

LSchwratz [185]
va
J.Kopecky
[184] d
Rumani, Nam
1978
d Nga xuit hien nhdm
ciia
HHJKHHH
CB,
anmTewH
H.A.
15
[141]
va nhdm
eiia roneH6ep
B.E va
PoaeHd/iMT
A.B.
[135].
Ndi chung, van de nay cdn
rai
mdi ddi vdi eac nude Ddng Nam A va
vdi
nude
ta thi cang mdi me.
Ngay nay,
vice
nghien
ciiu ''Mui

nhit dinh". Tuy vay, viec
ling
dung quan he eiu triie - tac dung dinh lupng dang
sap xep lai chinh ndi dung eua nganh hda y.
0.5.
Nhiing md hinh toan hoc nghien cuu
vSn
de QSAR
Dudi day tdi xin gidi thieu nhiing net cd ban eua mpt sd cac md hinh toan
hoac phuong phap toan thudng dupe dung de nghien
eiiu
vin d6 mdi lien quan
giOa
"eiu triic - tac dung", va se gidi thieu ky hdn ve hai md hinh eua
Free-Willson
va
ciia
Corwin Hansch la hai md hinh
dupe sii
dung trong ban luan
an nay.
a)-Phurang
phap nhan dang
-pharang
phap phan tich cdu
triic
con
Ca hai giai phap nay dua tren gia
thi6t
rang tac dung sinh hpc cua vat

(T),
tiicla:
''- '
-f
(3)
Khi
sii
dung he mieu ta
ciia
su ma hda
tiing
manh [58] la he ed kha nang
phan biet 1.200 manh khac nhau eua eiu triie la cac nhdm chiic, eac chuoi chiic,
eac vong chuc v.v va 110 dang ket hdp khac nhau
ciia
chiing da de xuit dude
viec hinh
thiie
hda va mpt chudng trinh may tinh cho phep xac dinh L cho cac
hdp chat khac nhau kha
Idn
ve eiu tao hda ho
•
vdi mpt loai tac dung sinh hpc da
bi6t ed so sanh vdi cac hpp chit dupe dem ra phan tich.
b)-Gidi phap ve cdc lirang
tur
thong ke [55, 141].
De cd dude mpt md hinh tinh toan ngudi ta da dua nhiing gia thiet sau day:
1-

ciia
chit dd d nhung
noi cdn lai.
Theo nhung gia thiet
dd,phuong
trinh xuit phat ed the bieu thi d dang:
d[BR]
dt
= kCopip2
(4)
Trong dd:
k
la
he sd ti le
Co
la ndng dp ban dau cua chit
pi
sac xuit hoan thanh giai doan dua chit tdi bp nhan
p2
sac xuit lien ket
ciia
chit
vdi
bp nhan
17
-cjiOii
T
1
:
*.

tii di the eua vat chit
dupe
hip phu. Ddi vdi giai phap nay cdn ehua cd nhieu sd
Heu
de tin cay. Ngay nay mdi chi cd the udc lupng dupe tinh uu viet ve nguyen tic
ciia
phuong
phaj
ma thdi, dd la
n.iCfng
thdng sd can thiet nhu tinh thim lipid , sd
sdng
ciia
cac nhdm phan
ling
dupe
de
xuit nghien
ciiu,
ed the la kha
d^
dang xac
dinh dude bang thue nghiem,
c)
Ifng
dung phan tich nhan td de tim hieu quan he cdu
true ~tdc
dung
De cd the giai bai toan ve mdi lien quan giiia eiu triic - tac dung mpt
each chat che thi can thiet phai xet tdi tit ca mpi qua trinh sinh ly cd the cd va

ddi k ;
U(i,j)
la nhan td j eua trudng hdp i ; V(j,k) la nhan td bien thien j
ciia
b\6n
sd da cho k. Tong dupe
liy
theo mpi nhan td j la
nhOng
nhan td
dupe
xem la quan
trpng. Trudng hpp rieng cua mdi lien quan eiu triic - tac dung ma ta quan tam la:
18