Reviews
The Role of Natural Product Chemistry in Drug Discovery †
Mark S.Butler*
MerLion Pharmaceuticals,1Science Park Road,The Capricorn #05-01,Singapore Science Park II,Singapore 117528Received April 27,2004
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Although traditionally natural products have played an important role in drug discovery,in the past few years most Big Pharma companies have either terminated or considerably scaled down their natural product operations.This is despite a significant number of natural product-derived drugs being ranked in the top 35worldwide lling ethical drugs in 2000,2001,and 2002.There were 15new natural product-derived drugs launched from 2000to 2003,as well as 15natural product-derived compounds in Pha III clinical trials or registration at the end of 2003.Recently,there has been a renewed interest in natural product rearch due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as immunosuppression,anti-infectives,and metabolic dias.To continue to be competitive with other drug discovery methods,natural product rearch needs to continually improve the speed of the screening,isolation,
and structure elucidation process,as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.
Introduction
For thousands of years medicine and natural products (NPs)have been cloly linked through the u of tradi-tional medicines and natural poisons.1-5Clinical,pharma-cological,and chemical studies of the traditional medi-cines,which were derived predominantly from plants,were the basis of most early medicines such as aspirin (1),digitoxin (2),morphine (3),quinine (4),and pilocarpine (5).1-5
The discovery of antibacterial filtrate “penicillin”by Fleming in 1928,re-isolation and clinical studies by Chain,Florey,and co-workers in the early 1940s,and com-mercialization of synthetic penicillins revolutionized drug discovery rearch.6-9Following the success of penicillin,drug companies and rearch groups soon asmbled large microorganism culture collections in order to discover new antibiotics.The output from the early years of this anti-biotic rearch was prolific and included examples such as streptomycin (6),chloramphenicol (7),chlortetracycline (8),cephalosporin C (9),erythromycin (10),and vancomycin (11).1,4,8,9All of the compounds,or derivatives thereof,are still in u as drugs today.
One of the next breakthroughs in drug discovery was the u of mechanism-bad screening for bioassay-guided fractionation.Through continual improvement of screening formats,reagent production,robotics,and data manage-ment,mechanism-bad screening has since become the mainstay of high-throughput screening (HTS).Some of the first compounds identified in the early 1970s using mech-anism-bad screening methods included the -lactama inhibitor clavulanic acid (12)from Streptomyces cla-vuligerus 10and the HMG-CoA reducta inhibitor meva-statin (13)(then named ML-236B)from Penicillium citri-num .11Mevastatin (13)(then also named compactin)was also reported as an antifungal agent from P.brevicompac-tum .12A mixture of clavulanic acid (12)and amoxicillin (14)(the combination is called Augmentin)is still being ud today as a front line antibiotic,while mevastatin (13)and lovastatin (15)were the lead compounds for a ries of antilipidemic drugs collectively known as the “statins”(Figure 1).13,14
Status of Natural Products in Drug Discovery Today
Despite competition from other drug discovery methods,NPs are still providing their fair share of new clinical candidates and drugs.This was demonstrated recently by Newman,Cragg,and Snader,who analyzed the number of NP-derived drugs prent in the total drug launches from 1981to 2002.15,16They concluded that NPs were still a significant source of new drugs,especially in the anti
cancer and antihypertensive therapeutic areas.15In another study,Proudfoot reported that 8out of 29small molecule drugs launched in 2000were derived from NPs or hormones and concluded that HTS did not have a significant impact on the derivation of the drugs.17
NP-derived drugs are well reprented in the top 35worldwide lling ethical drug sales of 2000,2001,and 2002
†
Bad on a Matthew Suffness Award lecture prented at the 43rd Annual Meeting of the American Society of Pharmacognosy and 3rd Monroe Wall Symposium,New Brunswick,NJ,July 27-31,2002.
*To whom correspondence should be addresd.Tel:+65-68295611.Fax:+6568295601.E-mail:
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©2004American Chemical Society and American Society of Pharmacognosy
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(Table 1and Figure 2).The percentage of NP-derived drugs was 40%in 2000and remained approximately constant at 24%in 2001and 26%in 2002.Therefore,in addition to being a proven and important source of drug leads,NP-derived drugs also contribute significantly to the profit-ability of many companies.
There has also been a steady introduction of new NP and NP-derived drugs in the United States,Eur
ope,and Japan from 2000to 2003(Table 2).A total of 15were launched (one in 2000,four in 2001,five in 2002,and five in 2003),which included new drug types such as the antimalarial arteether (16),18,19the echinocandin-derived antifungal caspofungin (20),20,21the anti-Alzheimer’s drug galan-tamine (galanthamine)(25),22,23,28and the antibacterial lipopeptide daptomycin (38).25-27,29Also noteworthy was the launch of the biologic gemtuzumab ozogamicin (40)(Mylotarg,Wyeth)in 2000,32which is a conjugate of recombinant humanized IgG4kappa antibody and cali-cheamicin (41),33an actinomycetes-derived antibiotic of the ene-diyne class.34The drug works by releasing a cali-cheamicin derivative from the antibody that binds to DNA in the minor groove,resulting in DNA double-strand breakage and cell death.32The developers of gemtuzumab ozogamicin (40)were awarded the 2003Discoverers Award from the Pharmaceutical Rearch and Manufacturers of America (PhRMA).35Drugs with links to NPs and tho derived from hormones and protein fragments launched since 2000include bivalirudin (2000)as an anticoagulant (lead:hirudin),18,19atosiban (2000)for preterm labor (lead:pituitary hormone oxytocin),19ganirelix acetate for female infertility (2000)(lead:luteinizing hormone-releas-ing hormone [LH-LR]),18,19taltirelin (2000)as a CNS
Figure 1.Statin class of antilipidemic drugs derived from the lead compound mevastatin (compactin,ML-236B)(13).
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Reviews
stimulant (lead:thyrotropin-releasing hormone [TRH]),17-19nestiritide (2001)as a treatment for acute decongestive heart failure (lead:recombinant form),20acemannan (2001)for wound healing (lead:manno-galacto acetate isolated from Aloe vera ),21fondaparinex sodium (2002)as an antithrombotic (lead:heparin),21,22,24abarelix (2003)for advanced prostate cancer (lead:gonadotropin releasing hormone [GnRH]),25-27and enfuviritide (2003)for treat-ment of HIV infection (lead:viral transfusion protein gp120).25-27,36
In 1998,Shu published a review on NPs in drug development from an industrial perspective listing most compounds that were then in clinical trials.37In that review,NP-derived drugs were well reprented in the anticancer,anti-infectives,immunosuppression,and neu-
rological dia therapeutic areas,and some of the compounds have since progresd further into clinical trials or onto the market.There were 15NP or NP-derived drugs in Pha III clinical trials or registration as of December 31,2003(Table 3).Trabectedin (66),which was filed in Europe for treatment of soft tissue sarcoma but was rejected in October 2003,is currently being studied as a single agent and in combination in other cancer indications with a scheduled launch in 2006.38The launch of orita-vancin (59),which was scheduled for 2005,also may be delayed,as there have been problems with its manufac-ture.39Anidulafungin (42),dalbavancin (44),everolimus (50),exatecan (52),rubitecan (62),and ziconotide (70)are scheduled for filing and/or launch in 2004,while FTY720(54),ramoplanin (61),and tigecycline (63)are scheduled for 2005,M6G (58)for 2006,and vinflunine (67)for 2007.There is no scheduled launch date available for edotecarin (46)and ixabepilone (56).
Current State of Industrial Natural Product Rearch
Drug discovery is a complex,interdisciplinary pursuit of chemistry,pharmacology,and clinical sciences,which has benefited humankind immenly over the last 100years.40,41Although drug discovery has been traditionally a difficult and expensive process,the amount of money currently being invested in R&D and clinical development has skyrocketed,while the output of newly launched
drugs has fallen.42-44This has prompted much discussion as to why this has occurred and how this will effect the future of the industry.45-47However,there may be hope on the horizon with a record number of new products entering the Pharmaprojects R&D databa in 2002-2003.48
Table 1.Top 35Worldwide Ethical Drug Sales for 2000,2001,and 2002a with Natural Product-Derived Drugs in Blue,b Biologically Derived Drugs in
Magenta,c and Synthetically Derived Drugs in Black d
a
Top 35worldwide ethical drug sales data supplied by Wood Mackenzie,Boston,MA.b NP-derived indicates that the drug is either a NP,a misynthetic derivative of a NP,or a synthetic drug that is modeled on a NP pharmacophore.c Biologically derived indicates that the drug is hormone or protein derived.d Erythropoietin is sold by both Johnston &Johnston (J&J)and Amgen,while pravastatin is marketed in Japan by Sankyo and the United States by Bristol-Myers Squibb (BMS).
Figure 2.Percentage of NP and NP-derived,biologic-derived,and synthetic-derived drugs in the top 35worldwide ethical drug sales for 2000,2001,and 2002(data derived from Table 1with “Interferon R -
2b +ribarvarin”counted as a biologic,“Salmeterol +Fluticasone pro-pionate”as NP-derived,and erythropoietin and pravastatin counted only once per year).
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T a b l e 2.N P o r N P -D e r i v e d D r u g s a L a u n c h e d i n E i t h e r t h e U n i t e d S t a t e s ,E u r o p e ,o r J a p a n i n 2000-200318-27
y e a r n a m e
l e a d s t r u c t u r e
c o m p a n y (o r i g i n a t o r )
d i s
e a s e m e c h a n i s m o
f a c t i o n m e t h o d o f m a n u f a c t u r e a n d o r i
g i n a l s o u r c e
任性 英文2000
a r t e e t h e r (16)(A r t e m o t i l )
a r t e m i s i n i n (17)
A r t e c e f
B V (
C e n t r a l
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D r u g I n s t i t u t e )
a n t i m a l a r i a l t h o u g h t t o i n v o l v e h e m e d e t o x i f i c a t i o n s e m i s y n t h e t i c a n d t e m p l a t e a r t e m i s i n i n o r i g i n a l l y i s o l a t e d f r o m t h e p l a n t A r t e m i s i a a n n u a 2001e r t a p e n e m (18)(I n v a n z )t h i e n a m y c i n (19)
M e r c k (A s t r a Z e n e c a )
a n t i
transcendental
b a
c t e r i a l b a c t e r i a l c e l l w a l l s y n t h e s i s i n h i b i t o r
s y n t h e t i c ;s t r u c t u r e b a s e d o n t h i e n a m y c i n o r i g i n a l l y i s o l a t e d f r o m S t r e p t o m y c e s c a t t l e y a 2001
c a s p o f u n g i n (20)(C a n c i
d a s )
p n e u m o c a n d i n B (21)
M e r c k (M e r c k )
a n t i f u n g a l 1,3- -D -g l u c a n s y n t h e s i s i n h i
b i t o r s e m i s y n t h e t i
c a n
d t
e m p l a t e p n e u m o c a n d i n B o r i g i n a l l y i s o l a t e d
f r o m t h e f u n
open up your dreamg u s G l a r e a l o z o y e n s i s 2001
t e l i t h r o m y c i n (22)(K e t e k )
e r y t h r o m y c i n (10)
咆哮的意思
A v e n t i s (A v e n t i s )a n t i b a c t e r i a l i n h i b i t i o n o f p r o t e i n s y n t h e s i s
s e m i s y n t h e t i c a n d t e m p l a t e e r y t h r o m y c i n o r i g i n a l l y i s o l a t e d f r o m S a c c h a r o p o l y s p o r a e r y t h r a e a (f o r m a l l y S t r e p t o m y c e s e r y t h r e u s )2001
p i m e c r o l i m u s (23)(E l i d e l )
a s c o m y c i n (24)
N o v a r t i s (N o v a r t i s )
a t o p i c d e r m a t i t i s
t h o u g h t t o i n h i b i t T c e l l a c t i v a t i o n a n d p r e v e n t s r e l e a s e o f i n f l a m m a t o r y c y t o k i n e s s e m i s y n t h e t i c a n d t e m p l a t e a s c o m y c i n o r i g i n a l l y i s o l a t e d f r o m S t r e p t o m y c e s h y g r o s c o p i c u s v a r .a s c o m y c e t i c u s 2002b
g a l a n t a m i n e (25)(R e m i n y l )
n a t u r a l p r o d u c t
J o h n s o n &J o h n s o n (T r a d .M e d .f r o m E a s t e r n E u r o p e )A l z h e i m e r ’s d i s e a s e
t h o u g h t t o i n v o l v e i n h i b i t i o n o f a c e t y l c h o l i n e s t e r a s e
s y n t h e t i c ;N P o r i g i n a l l y i s o l a t e d f r o m t h e p l a n t G a l a n t h u s s p p .a n d l a t e r f r o m N a r c i s s u s s p p .2002m i c a f u n g i n (26)(F u n g u a r d )F R 901379(27)
F u j i s a w a (F u j i s a w a )
a n t i f u n g a l
1,3- -D -g l u c a n s y n t h e s i s i n h i b i t o r
s e m i s y n t h e t i c a n d t e m p l a t e F R 901379i s o l a t e d f r o m t h e f u n g u s C o l e o p h o m a e m p e t r i 2002
画眼妆步骤a m r u
b i
c i n h y
d r o c h l o r i d
e (28)(C a l s e d )
d o x o r u b i c i n (29)
S u m i t o m o (S u m i t o m o )
a n t i c a n c e r
i n h i b i t i o n o f t o p o i s o m e r a s e I I
s y n t h e t i c a n d b a s e d u p o n d o x o r u b i c i n ,w h i c h w a s o r i g i n a l l y d e r i v e d f r o m S t r e p t o m y c e s p e u c e t i u s 2002
b i a p e n e m (30)(O m e g a
c i n )
t h i e n a m y c i n (19)M e i j i S e i k a (W y e t h )
a n t i
b a
c t e r i a l
b a
c t e r i a l c e l l w a l l s y n t h e s i s i n h i b i t o r
s y n t h e t i c ;s t r u c t u r e b a s e d o n t h i e n a m y c i n o r i g i n a l l y i s o l a t e d f r o m S t r e p t o m y c e s c a t t l e y a 2002
n i t i s i n o n e (31)(O r f a d i n )
l e p t o s p e r m o n e (32)
R a r e D i s e a s e s T h e r a p e u t i c s (A s t r a Z e n e c a )
a n t i t y r o s i n a e m i a
i n h i b i t i o n o f 4-h y d r o x y p h e n y l p y r u v a t e d i o x y g e n a s e
s y n t h e t i c .s t r u c t u r e b a s e d o n l e p t o s p e r m o n e o r i g i n a l l y i s o l a t e d f r o m t h e p l a n t C a l l i s t e m o n c i t r i n u s a n d r e l a t e d t o t r i k e t o n e h e r b i c i d e s 2003
m i g l u s t a t (33)(Z a v e s c a )
1-d e o x y n o j i r i m y c i n (34)
A c t e l i o n /T e v a (C e l l T e c h )
t y p e 1G a u c h e r d i s e a s e
i n h i b i t i o n o f g l u c o s y l c e r a m i d e s y n t h a s e
s y n t h e t i c ;l e a d c o m p o u n d 1-d e o x y n o j i r i m y c i n i s o l a t e d f r o m S t r e p t o m y c e s t r e h a l o s a t i c u s a n d v a r i o u s p l a n t s 2003m y c o p h e n o l a t e s o d i u m (35)(M y f o r t i c )n a t u r a l p r o d u c t
N o v a r t i s c
i m m u n o s u p p r e s s i o n
i n h i b i t o r o f i n o s i n e m o n o p h o s p h a t e d e h y d r o g e n a s e s y n t h e t i c ;N P o r i g i n a l l y i s o l a t e d f r o m t h e f u n g u s P e n i c i l l i u m b r e v i c o m p a c t u m 2003
r o s u v a s t a t i n (36)(C r e s t o r )
m e v a s t a t i n (13)
A s t r a Z e n e c a (S h i o n o g i &C o )d y s l i p i d e m i a
i n h i b i t i o n o f H M G -C o A r e d u c t a s e
s y n t h e t i c ;s t r u c t u r e b a s e d o n m e v a s t a t i n o r i g i n a l l y i s o l a t e d f r o m P e n i c i l l i u m c i t r i m u n a n d P .b r e v i c o m p a c t u m 2003
p i t a v a s t a t i n (37)(L i v a l o )
m e v a s t a t i n (13)
S a n k y o /K o w a (K o w a /N i s s a n C h e m i c a l )d y s l i p i d e m i a
evergrande
i n h i b i t i o n o f H M G -C o A r e d u c t a s e
s y n t h e t i c ;s t r u c t u r e b a s e d o n m e v a s t a t i n o r i g i n a l l y i s o l a t e d f r o m P e n i c i l l i u m c i t r i m u n a n d P .b r e v i c o m p a c t u m 2003
d a p t o m y c i n (38)(C u b i c i n )
n a t u r a l p r o d u c t
C u b i s t (L i l l y )
a n t i
b a
c t e r i a l
i n h i b i t i o n o f p r o t e i n ,D N A a n d R N A s y n t h e s i s
n a t u r a l p r o d u c t t h a t i s i s o l a t e d f r o m S t r e p t o m y c e s r o s e o s p o r u s
a
O t h e r d r u g s l a u n c h e d w i t h c o n n e c t i o n t o N P s :V i t a m i n D :m a x a c a l c i t o l (2000)a n d f a l e c a l c i t r i o l (2001).S t e r o i d :d r o s p i r e n o n e (2000),e x e m e s t a n e (2000),t r i m e g e s t o n e (2001),f u l v e s t r a n t (2002),n o r e l g e s t r o m i n (2002),a n d d u t a s t e r i d e (2003).T r y p t a m i n e :a l m o t r i p t a n (2000),a l o s e t r o n h y d r o c h l o r i d e (2000),r a m a t r o b a n (2000),e l e t r i p a n (2001),t a g a s e r o d m a l e a t e (2001),a n d f r o v a t r i p t a n (2002).P r o s t a g l a n d i n :b i m a t o p r o s t (2001),t r a v o p r o s t (2001),a n d t r e p r o s t i n i l s o d i u m (2002).b G a l a n t a m i n e (g a l a n t h a m i n e )(25)w a s l a u n c h e d i n A u s t r i a i n 1996a s N i v a l i n a n d t h e n i n 2002a s R e m i n y l i n E u r o p e a n d t h e U n i t e d S t a t e s .28c M y c o p h e n o l i c a c i d (35)w a s t h e f i r s t a n t i b a c t e r i a l d i s c o v e r e d i n 1893.4,30I t s m o f e t i l d e r i v a t i v e (39)(C e l l C e p t ,R o c h e )w a s l a u n c h e d i n 1995a s a n i m m u n o s u p p r e s s a n t .31
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Given that NPs have historically provided many novel drugs leads,one would assume that NPs would still play a pivotal role in the drug discovery strategy of Big Pharma. However,most Big Pharma companies have terminated or significantly scaled down their NP operations in the last 10years.49-52To a certain extent the downsizing or termination of the NP rearch programs has been offt by biotech companies offering NP-related rvices such as pure NP libraries and more traditional extract bad screening rvices.53-58To better understand why Big Pharma has scaled down its NP rearch programs,it is prudent to examine the differences between the pharma-ceutical industry of today and that of10-20years ago (Table4).
The advent of combinatorial chemistry about15years ago created huge excitement in the pharmaceutical indus-try,and most Big Pharma companies quickly changed their drug discovery strategies to include a significant proportion of combinatorial chemistry.66,67The impending structure of the human genome and the promi of a plethora of new targets added to the excitement of the time.The basic premi was that combinatorial chemistry would generate
Chart1
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2145雅思补习
