《天然药物化学》课程参考文献（天然药物研究与开发）Mother Nature’s gifts to diseases of man - the impact of natural products on anti-infective, anticholestemics and anticancer drug discovery.pdf_大学文库

Mother nature's gifts to diseases of man Abstract This chapter is designed to demonstrate that compounds derived from nature are still in the forefront of drug discovery in diseases such as microbial and parasitic infections,carcinomas of many types and control of cholesterol/lipids in man.In each disease area we have provided short discussions of past,present and future agents,in general only considering compounds currently in clinical Phase Il or later,that were/are derived from nature's chemical skeletons. Finishing with a discussion of the current and evolving role(s)of microbes(bacteria and fungi)in the production of old and new agents ostensibly produced by higher organisms. 1 Introduction to natural products Throughout the ages humans have relied on nature for their basic needs and not least,their medicines.Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years.The first records,written on clay tablets in cuneiform,are from Meso- potamia and date from about 2600 BCE,while Egyptian medicine dates from about 2900 BCE,with the best known Egyptian pharmaceutical record being the Ebers Papynus dating from 1500 BCE [1,2].The Chinese Materia Medica has been extensively documented over the centuries,with the first record (Wu Shi Er Bing Fang),containing 52 prescriptions,dating from about 1100 BCE [3,4]though records from the Pent'sao are reputed to be even earlier (-2700 BCE)and documentation of the Indian Ayurvedic system dates from about 1000 BCE (Susruta and Charaka)[5,6].In the ancient Western world, the Greeks contributed substantially to the rational development of the use of herbal drugs.The philosopher and natural scientist,Theophrastus (-300 BCE),in his History of Plants,dealt with the medicinal qualities of herbs and Dioscorides,a Greek physician(100 CE),during his travels with Roman armies,recorded the collection,storage and use of medicinal herbs. Galen(130-200 CE),who practiced and taught pharmacy and medicine in Rome,published no less than 30 books on these subjects and is well known for his complex prescriptions and formulas used in compounding drugs, sometimes containing dozens of ingredients('galenicals'). During the Dark and Middle Ages(5th to 12th Centuries),it was the Arabs who were responsible for the preservation of much of the Greco- Roman expertise and for expanding it to include the use of their own resources,together with Chinese and Indian herbs unknown to the Greco- Roman world.The Arabs were the first to establish privately owned drug 3

Mother nature’s gifts to diseases of man 3 Abstract This chapter is designed to demonstrate that compounds derived from nature are still in the forefront of drug discovery in diseases such as microbial and parasitic infections, carcinomas of many types and control of cholesterol/lipids in man. In each disease area we have provided short discussions of past, present and future agents, in general only considering compounds currently in clinical Phase II or later, that were/are derived from nature’s chemical skeletons. Finishing with a discussion of the current and evolving role(s) of microbes (bacteria and fungi) in the production of old and new agents ostensibly produced by higher organisms. 1 Introduction to natural products Throughout the ages humans have relied on nature for their basic needs and not least, their medicines. Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years. The first records, written on clay tablets in cuneiform, are from Mesopotamia and date from about 2600 BCE, while Egyptian medicine dates from about 2900 BCE, with the best known Egyptian pharmaceutical record being the Ebers Papyrus dating from 1500 BCE [1, 2]. The Chinese Materia Medica has been extensively documented over the centuries, with the first record (Wu Shi Er Bing Fang), containing 52 prescriptions, dating from about 1100 BCE [3, 4] though records from the Pent’sao are reputed to be even earlier (~2700 BCE) and documentation of the Indian Ayurvedic system dates from about 1000 BCE (Susruta and Charaka) [5, 6]. In the ancient Western world, the Greeks contributed substantially to the rational development of the use of herbal drugs. The philosopher and natural scientist, Theophrastus (~300 BCE), in his History of Plants, dealt with the medicinal qualities of herbs and Dioscorides, a Greek physician (100 CE), during his travels with Roman armies, recorded the collection, storage and use of medicinal herbs. Galen (130–200 CE), who practiced and taught pharmacy and medicine in Rome, published no less than 30 books on these subjects and is well known for his complex prescriptions and formulas used in compounding drugs, sometimes containing dozens of ingredients (‘galenicals’). During the Dark and Middle Ages (5th to 12th Centuries), it was the Arabs who were responsible for the preservation of much of the GrecoRoman expertise and for expanding it to include the use of their own resources, together with Chinese and Indian herbs unknown to the GrecoRoman world. The Arabs were the first to establish privately owned drug 3

Mark S.Butler and David J.Newman stores in the 8th Century and the Persian pharmacist,physician,philoso- pher and poet,Avicenna,contributed much to the sciences of pharmacy and medicine through works such as Canon Medicinae,regarded as "the final codification of all Greco-Roman medicine".A comprehensive review of the history of medicine may be found on the National Library of Med- cine's History of Medicine'homepage [7] That natural products(NPs)are still 'alive and well'as both direct and indirect sources of leads to drugs against all classes of disease is shown quite dramatically in Figure 1,which is taken from the third review in the series by Newman et al.,covering sources of drugs approved against all diseases by the Food and Drug Administration (FDA)or their equivalents in other countries from 1January 1981 to 30 June 2006 [8].The influence of natural products directly (N)or slight modifications (ND)are quite obvious,and when their use as sources of pharmacophores(or privileged structures that may be utilized as isosteres of naturally occurring chemical skeletons,S" S*/NM and S/NM being the classifications for these [9])then the continued nfluence is quite striking. Rather than the customary chemical usage of discussing compounds subdivided by chemical structures(skeletons)we have elected to classify by disease classes.One major reason for this is that nowadays it is quite com- mon for a drug to be developed for one disease and then to find its'niche' as a treatment for another separate disease or even to spawn derivatives that have yet a third or fourth potential area in which to be useful. An excellent example of this is in the case of the fungal secondary metabolite,sirolimus(rapamycin)(1).Originally developed as an antifun- gal agent by Ayerst(now Wyeth),it was approved as an immunosuppres- sive drug(Rapamune)and a derivative,temsirolimus(2),is in a multiplic- ity of trials against a variety of cancers(see Section 4). As a result,we are discussing natural products and their derivatives, including modified nucleosides,some peptides depending upon the dis ease area and a number of drugs that contain the 'warhead of the natural product'but have modified lipophilic structures giving different pharma codynamics/pharmacokinetics(i.e.,the variations on mevastatin(3)that led to the formally synthetic anticholesterolemics such as atorvastatin(4) (see Section 3). The format of each section will provide a brief historical coverage,fol- lowed by drugs in current use and a short description of each NP or NP. 4

Mark S. Butler and David J. Newman 4 stores in the 8th Century and the Persian pharmacist, physician, philosopher and poet, Avicenna, contributed much to the sciences of pharmacy and medicine through works such as Canon Medicinae, regarded as “the final codification of all Greco-Roman medicine”. A comprehensive review of the history of medicine may be found on the National Library of Medicine’s ‘History of Medicine’ homepage [7]. That natural products (NPs) are still ‘alive and well’ as both direct and indirect sources of leads to drugs against all classes of disease is shown quite dramatically in Figure 1, which is taken from the third review in the series by Newman et al., covering sources of drugs approved against all diseases by the Food and Drug Administration (FDA) or their equivalents in other countries from 1 January 1981 to 30 June 2006 [8]. The influence of natural products directly (N) or slight modifications (ND) are quite obvious, and when their use as sources of pharmacophores (or privileged structures that may be utilized as isosteres of naturally occurring chemical skeletons, S*; S*/NM and S/NM being the classifications for these [9]) then the continued influence is quite striking. Rather than the customary chemical usage of discussing compounds subdivided by chemical structures (skeletons) we have elected to classify by disease classes. One major reason for this is that nowadays it is quite common for a drug to be developed for one disease and then to find its ‘niche’ as a treatment for another separate disease or even to spawn derivatives that have yet a third or fourth potential area in which to be useful. An excellent example of this is in the case of the fungal secondary metabolite, sirolimus (rapamycin) (1). Originally developed as an antifungal agent by Ayerst (now Wyeth), it was approved as an immunosuppressive drug (Rapamune®) and a derivative, temsirolimus (2), is in a multiplicity of trials against a variety of cancers (see Section 4). As a result, we are discussing natural products and their derivatives, including modified nucleosides, some peptides depending upon the disease area and a number of drugs that contain the ‘warhead of the natural product’ but have modified lipophilic structures giving different pharmacodynamics/pharmacokinetics (i.e., the variations on mevastatin (3) that led to the formally synthetic anticholesterolemics such as atorvastatin (4) (see Section 3). The format of each section will provide a brief historical coverage, followed by drugs in current use and a short description of each NP or NP- 4

Mark S.Butler and David J.Newman between various bacteria.The advent of the sulfonamides exemplified by Prontosil(5)led to the introduction of synthetic antibacterials with the first clinical efficacy report in 1933 and ultimately leading to the award of the Nobel Prize for Medicine in 1938 to Domagk.This could also be thought of as the first formal prodrug in the antibiotic field as the active principle sulfanilamide(6)is a structural analogue of para-aminobenzoic acid(PABA).PABA competitively inhibits dihydropteroate synthase,thus leading to inhibition of folic acid and bacterial death.So although syn- thesized in the absence of such knowledge,and for an entirely different purpose,it was in retrospect an isostere of a NP. We will briefly discuss the major chemical classes of natural antibiotics and give suitable references to articles which will go into much greater detail for the interested reader in each section. 2.1.1 B-Lactams Following the isolation and identification of penicillin G and then peni- cillin V in the UK and the USA in the early 1940s which was covered in detail in 1998 by Mateles in an excellent reprint entitled History of Penicillin Production [15],the number of penicillin-based molecules that have been produced by semi-and total synthesis to date is well over the 15,000 level. Most of these compounds have started with modification of the fermenta- tion product,6-amino-penicillanic acid(7),which also can be produced by a simple chemical or biochemical deacylation from penicillins.The number above is only indicative as a significant proportion of materials were never published,particularly from industry,as they had marginal or no significant activity over those that had been reported previously. In 1948,the ring-expanded version of penicillin,cephalosporin C,was reported from Cephalosporium sp.by Brotzu and its structure determined in 1961 by the Oxford Group 16,17.As with the penicillin nucleus,this ring expanded molecule also served as the building block(as its 7-amino cephalosporanic acid homologue)for many thousands of cephalosporins, with the first orally-active molecule,cephalexin(8)being introduced in 1970.Since that time,a multitude of cephalosporins have been syn- thesized with the aim of producing molecules that are more resistant to B-lactamases. 6

Mark S. Butler and David J. Newman 6 between various bacteria. The advent of the sulfonamides exemplified by Prontosil® (5) led to the introduction of synthetic antibacterials with the first clinical efficacy report in 1933 and ultimately leading to the award of the Nobel Prize for Medicine in 1938 to Domagk. This could also be thought of as the first formal prodrug in the antibiotic field as the active principle sulfanilamide (6) is a structural analogue of para-aminobenzoic acid (PABA). PABA competitively inhibits dihydropteroate synthase, thus leading to inhibition of folic acid and bacterial death. So although synthesized in the absence of such knowledge, and for an entirely different purpose, it was in retrospect an isostere of a NP. We will briefly discuss the major chemical classes of natural antibiotics and give suitable references to articles which will go into much greater detail for the interested reader in each section. 2.1.1 `-Lactams Following the isolation and identification of penicillin G and then penicillin V in the UK and the USA in the early 1940s which was covered in detail in 1998 by Mateles in an excellent reprint entitled History of Penicillin Production [15], the number of penicillin-based molecules that have been produced by semi- and total synthesis to date is well over the 15,000 level. Most of these compounds have started with modification of the fermentation product, 6-amino-penicillanic acid (7), which also can be produced by a simple chemical or biochemical deacylation from penicillins. The number above is only indicative as a significant proportion of materials were never published, particularly from industry, as they had marginal or no significant activity over those that had been reported previously. In 1948, the ring-expanded version of penicillin, cephalosporin C, was reported from Cephalosporium sp. by Brotzu and its structure determined in 1961 by the Oxford Group [16, 17]. As with the penicillin nucleus, this ring expanded molecule also served as the building block (as its 7-aminocephalosporanic acid homologue) for many thousands of cephalosporins, with the first orally-active molecule, cephalexin (8) being introduced in 1970. Since that time, a multitude of cephalosporins have been synthesized with the aim of producing molecules that are more resistant to `-lactamases

Mark S.Butler and David J.Newman 2.1.2 Actinomycins,aminoglycosides,tetracyclines and erythromycins Concomitantly with the early development of the penicillins,Waksman was working at Rutgers University in New Jersey in the late 1930s/early 1940s,specializing in investigation of the actinomycetes (which at that time were considered to be fungi),with the aim of finding a treatment for tuberculosis.His initial finding in 1940,however,was the identification of chromooligopeptides of the actinomycin class(e.g.,actinomycin D(11)). which though not useful as antibacterials,led to what was the first use of such secondary metabolites as a treatment for cancer(Wilms'tumor)[20]. In 1943,the aminoglycoside antibiotic streptomycin(12)was isolated from Streptomyces griseus and,in addition to being active against Myco- bacterium tuberculosis,was active against a wide range of other patho- nge mum otmnu a group they have a major biological Achilles heel in the sense that they are easily inactivated by plasmid-mediated acetylation or phosphorylation and multiply resistant organisms have evolved.However,aminoglycosides still have utility particularly in conjunction with B-lactams with whom they exhibit true synergy. The fourth series of molecules to be reported was a previously unknown molecule with four fused rings (a tetracycline).The parent molecule was not used to any great extent as an antibacterial but the naturally occurring chlorinated analogue,Aureomycin(13),was.This tetracycline skeleton has given rise to a large number of semi-synthetic molecules with three of these,doxycycline(14),minocycline(15)and tigecycline (16),being used today,particularly against the causative agent of Lyme disease. The macrolide antibiotics,exemplified by erythromycin (17),are as equally famous and long-lived as the other classes previously dis. cussed.Even today,erythromycin (17)is still prescribed,particularly for pediatric patients.This class of antibiotics has yet another claim to fame as it was one of the first molecules for which the biogenetic sys- tem was described in 1990 using classical mutation studies [21],which later developed into the system known as combinatorial biosynthesis whereby non-naturally occurring metabolites are made by 'mixing and matching'gene clusters [22].More current details can be found in the 8

Mark S. Butler and David J. Newman 8 2.1.2 Actinomycins, aminoglycosides, tetracyclines and erythromycins Concomitantly with the early development of the penicillins, Waksman was working at Rutgers University in New Jersey in the late 1930s/early 1940s, specializing in investigation of the actinomycetes (which at that time were considered to be fungi), with the aim of finding a treatment for tuberculosis. His initial finding in 1940, however, was the identification of chromooligopeptides of the actinomycin class (e.g., actinomycin D (11)), which though not useful as antibacterials, led to what was the first use of such secondary metabolites as a treatment for cancer (Wilms’ tumor) [20]. In 1943, the aminoglycoside antibiotic streptomycin (12) was isolated from Streptomyces griseus and, in addition to being active against Mycobacterium tuberculosis, was active against a wide range of other pathogenic organisms. Further work over the next twenty or so years yielded a large number of similar glycosidic-based antibacterials. Unfortunately, as a group they have a major biological Achilles heel in the sense that they are easily inactivated by plasmid-mediated acetylation or phosphorylation and multiply resistant organisms have evolved. However, aminoglycosides still have utility particularly in conjunction with `-lactams with whom they exhibit true synergy. The fourth series of molecules to be reported was a previously unknown molecule with four fused rings (a tetracycline). The parent molecule was not used to any great extent as an antibacterial but the naturally occurring chlorinated analogue, Aureomycin® (13), was. This tetracycline skeleton has given rise to a large number of semi-synthetic molecules with three of these, doxycycline (14), minocycline (15) and tigecycline (16), being used today, particularly against the causative agent of Lyme disease. The macrolide antibiotics, exemplified by erythromycin (17), are as equally famous and long-lived as the other classes previously discussed. Even today, erythromycin (17) is still prescribed, particularly for pediatric patients. This class of antibiotics has yet another claim to fame as it was one of the first molecules for which the biogenetic system was described in 1990 using classical mutation studies [21], which later developed into the system known as combinatorial biosynthesis whereby non-naturally occurring metabolites are made by ‘mixing and matching’ gene clusters [22]. More current details can be found in the

Mark S.Butler and David J.Newman Aventis)(20)[28,29],biapenem (2002,Omegacin,Meiji)(21)[30,31], daptomycin(20,)(1)[31,doripenem (00,Fini- bax,Shionogi Co;Phase III (US),J&J)(22)[33,34]and tigecycline (2005,Tygacil Wyeth)(16)[35-39].Ertapenem(19),biapenem(21)and doripenem(22)are carbapenem antibiotics(part of the B-lactam family), which are produced synthetically but their lead structure was the NP thienamycin(23).Tigecycline(16)is a semi-synthetic derivative of tetra- cycline,while telithromycin(20)is a semi-synthetic derivative of erythro- mycin(17).Daptomycin(18)is a lipopeptide NP used for the treatment of complicated skin and skin structure infections(cSSSi)and Staphylococcus aureus bloodstream infections or bacteremia including right-sided infec- tive endocarditis.In terms of sales,daptomycin (18)has had the most successful launch for an IV antibiotic in US history.Daptomycin(18)rep- resents only one of three new antibiotic classes launched since 1970:the other two being the topical antibiotic NP mupirocin(24)in 1985 and the synthetic oxazolidinone linezolid(25)in 2000. There are total of four B-lactams,two cephalosporins,ceftobripole medo caril (26)and ceftaroline acetate (27),and two carbapenems,R1558(28) and tebipenem(29),in Phase II or Phase IlI clinical trials or undergoing drug registration.Ceftobiprole medocaril(26)is a fourth generation cepha- losporin that has potent bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA)and penicillin resistant Streptococcus pneumoniae (PRSP)[40].Basilea and Johnson and Johnson Pharmaceutical Research and Development LLC (&)are evaluating ceftobiprole medocaril(26)for the treatment of cSSSi,nosocomial pneumonia and hospitalized community acquired pneumonia(CAP)in various Phase III trials.Ceftaroline (PPI-0903, TAK-599)(27)is being evaluated by Cerexa in Phase II trials and both cefto- biprole(26)and ceftaroline(27)have been granted FDA fast-track status [40, 41].The carbapenems R1558(Ro4908463,CS-023,Sankyo and Roche)(28) [40,42]and tebipenem pivoxil (ME-1211,Meiji Seika)(29)are being evalu ated in Phase II clinical trials as a broad spectrum antibiotics [43]. There are three semi-synthetic glycopeptides [32,44,45],dalbavancin (30),telavancin(31)and oritavancin (32),in late stage clinical investiga- tion and their antibacterial mechanism is through inhibition of cell wall production.Dalbavancin (Zeven)is a semi-synthetic derivative of BO- A40926 factor(33)[46],a glycopeptide related to teicoplanin (34),and a New Drug Application(NDA)for the treatment of skin and soft tissue 10

Mark S. Butler and David J. Newman 10 Aventis) (20) [28, 29], biapenem (2002, Omegacin®, Meiji) (21) [30, 31], daptomycin (2003, Cubicin®, Cubist) (18) [24, 32], doripenem (2005, Finibax®, Shionogi & Co; Phase III (US), J&J) (22) [33, 34] and tigecycline (2005, Tygacil®, Wyeth) (16) [35–39]. Ertapenem (19), biapenem (21) and doripenem (22) are carbapenem antibiotics (part of the `-lactam family), which are produced synthetically but their lead structure was the NP thienamycin (23). Tigecycline (16) is a semi-synthetic derivative of tetracycline, while telithromycin (20) is a semi-synthetic derivative of erythromycin (17). Daptomycin (18) is a lipopeptide NP used for the treatment of complicated skin and skin structure infections (cSSSi) and Staphylococcus aureus bloodstream infections or bacteremia including right-sided infective endocarditis. In terms of sales, daptomycin (18) has had the most successful launch for an IV antibiotic in US history. Daptomycin (18) represents only one of three new antibiotic classes launched since 1970; the other two being the topical antibiotic NP mupirocin (24) in 1985 and the synthetic oxazolidinone linezolid (25) in 2000. There are total of four `-lactams, two cephalosporins, ceftobripole medocaril (26) and ceftaroline acetate (27), and two carbapenems, R1558 (28) and tebipenem (29), in Phase II or Phase III clinical trials or undergoing drug registration. Ceftobiprole medocaril (26) is a fourth generation cephalosporin that has potent bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA) and penicillin resistant Streptococcus pneumoniae (PRSP) [40]. Basilea and Johnson and Johnson Pharmaceutical Research and Development LLC (J&J) are evaluating ceftobiprole medocaril (26) for the treatment of cSSSi, nosocomial pneumonia and hospitalized community acquired pneumonia (CAP) in various Phase III trials. Ceftaroline (PPI-0903, TAK-599) (27) is being evaluated by Cerexa in Phase II trials and both ceftobiprole (26) and ceftaroline (27) have been granted FDA fast-track status [40, 41]. The carbapenems R1558 (Ro4908463, CS-023, Sankyo and Roche) (28) [40, 42] and tebipenem pivoxil (ME-1211, Meiji Seika) (29) are being evaluated in Phase II clinical trials as a broad spectrum antibiotics [43]. There are three semi-synthetic glycopeptides [32, 44, 45], dalbavancin (30), telavancin (31) and oritavancin (32), in late stage clinical investigation and their antibacterial mechanism is through inhibition of cell wall production. Dalbavancin (Zeven®) is a semi-synthetic derivative of B0- A40926 factor (33) [46], a glycopeptide related to teicoplanin (34), and a New Drug Application (NDA) for the treatment of skin and soft tissue