Chemistry Reference
In-Depth Information
O
OH
O
O
OH
OH
Me
Thr-D-Val-Pro
O
N
MeVal
MeGly
O
OMe
O
OH
O
Me
O
Me
Thr-D-Val-Pro
H
2
N
O
NH2
MeVal
MeGly
OH
Doxorubicin (
74
)
Dactinomycin (
75
)
CONH
2
N
NH
2
N
O
R
CONH2
N
NN
N
O
Me
Me
O
S
N
H
2
N
H
NH
N
O
O
O
NH
2
Me
O
OH
O
HO
H
2
N
OMe
N
S
O
OH
N
NH
NH
Me
HO
O
O
O
O
OH
OH
OH
Mitomycin C (
78
)
O
OH
O
NH
2
Bleomycin A
2
, R=CH
2
CH
2
CH
2
S+(CH
3
)
2
(
76
)
Bleomycin B
2
, R=CH
2
CH
2
CH
2
CH
2
NHC(NH)NH
2
, (
77
)
O
O
O
O
R
HO
R
N
O
O
N
N
S
O
O
O
N
N
Me
O
OH
Me
H
N
Me
Me
Me
H
Me
OMe
O
OMe
Me
N
Cl
Me
CO
2
Ph
NHMe
O
OH
O
Epothilone A, R = H (
82
)
Epothilone B, R = Me (
83
)
Salinosporamide A (
84
)
Staurosporine,R = H (
79
)
7-Hydrxystaurosporine, R =OH (
80
)
CGP41251 (
81
)
interesting biological activity, and clinically proven mode of action drew signif-
icant attention from the scientific community and led to a variety of approaches,
including combinatorial biosynthesis, chemical modifications, and total synthe-
sis, that permitted preparation of many derivatives with improved potency and
drug-like properties. A series of these compounds have entered human clinical
trials, and many are in the late stages of development. Epothilone discovery and
development has been reviewed (85).
Recent pursuit of marine microbial sources led to the isolation of salinospo-
ramide A (
84
). It is a
β
-lactone produced by the marine bacteria
Salinispora
tropica
and is a proteasome inhibitor (86). Mechanistically, it works by specific
covalent modification of the target. This compound has entered human clinical
development for treatment of multiple myeloma (87-89).
