有人询问对于肾癌细胞具有抑制生长作用的Englerin A衍生物是否有专利申请，结果有关专利文献数据库进行不全面的简要检索，得到了几项相关专利文献，有美国专利。欧洲专利、世界专利组织的专利，具体内容加下： Match Document Document Title Score 1 WO/2011/120886A1 A PROCESS FOR THE PREPARATION OF (-)-ENGLERIN A, AND ANALOGUES AND INTERMEDIATES THEREOF It is provided a process for the preparation of (-)-englerin A, as well as analogous compounds thereof, the process comprising transforming a compound of formula (II) wherein PG1 is an ether... 1000 2 WO/2012/084267A1 DERIVATIVES OF ENGLERIN FOR THE TREATMENT OF CANCER The present invention relates to compounds of the general Formula (I), which show a specific activity against cancer cell lines, the use of these compounds for prophylaxis and treatment of cancer... 630 3 WO/2009/088854A1 EPOXY-GUAIANE DERIVATIVES AND TREATMENT OF CANCER Disclosed are englerins and derivatives (I) thereof useful in the treatment of a number of cancers, particularly renal cancer, as well as pharmaceutical compositions and method of treating a... 410 4 EP2474550A1 Derivatives of Englerin for the treatment of cancer The present invention relates to compounds of the general formula (I) which show a specific activity against cancer cell lines, the use of these compounds for prophylaxis and treatment of cancer as... 407 5 US20100286259 EPOXY-GUAIANE DERIVATIVES AND TREATMENT OF CANCER Disclosed are englerins and derivatives (I) thereof useful in the treatment of a number of cancers, particularly renal cancer, as well as pharmaceutical compositions and method of treating a... 379 6 EP2235021B1 EPOXY-GUAIANE DERIVATIVES AND TREATMENT OF CANCER 120
参阅读物： 《屠呦呦2002年接受天津日报的采访报道》 http://past.tianjindaily.com.cn/docroot/200203/22/km02/22132801.htm http://blog.sciencenet.cn/home.php?mod=spaceuid=396469do=blogid=499867 Peters's Blog Conversations with myself – 8th November 2010 Miracle Chinese antimalarial threatened by human folly Whichever national newspaper you read in most countries at the present time, you are likely to see headlined the fate of probably the most important contemporary and, at the same time, oldest drug for the treatment of one of mankind’s deadliest infectious diseases, malignant tertian malaria. Experience has shown, especially since World War II, that malaria parasites have a remarkable capacity for learning how to overcome the drugs that are aimed at them. Sadly, Man being an unreliable and often unscrupulous species, many of the world’s market places are currently being flooded with fake, or otherwise unacceptable and often useless products, masquerading as antimalarials, antibiotics, anticancer drugs and so on. Although the use of drugs is only one method of managing malaria, it is vital to have at our disposal compounds with which we can save the lives of those who become infected by these dangerous organisms. As I have invested much of my life in the fight against this enemy I decided to offer you here and now a part personal, part technical account of artemisinin, the drug that I have studied with Chinese and many other colleagues for over 30 years. The following story that may soon appear as a section of my autobiography is so topical that I offer it now in the hope that it may contribute in some small way to the current campaign to “eliminate” malaria. As a realist, I use the term “hope” rather than “expectation”. Chinese scientists have devoted much effort to the development of a remarkable and extremely effective compound named artemisinin about which many inaccurate statements have been made. I hope here to set the record straight. My concern is that the value of artemisin is already being squandered. You must judge for yourselves. The medicinal value of a weed popularly called ‘Sweet Wormwood’, ‘Sweet Annie’ or ‘qing hao’ (Fig.1) ensured its place in traditional Chinese medicine for nearly two millenia. The ancient origin and modern history of its development since 1972, and its exploitation as one of the most potent antimalarials ever known, have only recently become the focus of worldwide scientific research that is leading to an outpouring of many papers on laboratory and clinical studies. Fig.1 Qing hao growing wild on a wall of the Forbidden City, Beijing The first report to draw the attention of scientists outside China to this research appeared in English in the Chinese Medical Journal in 1979 (Fig.2). It was this remarkable paper that immediately drew my attention to the revived study of malaria chemotherapy in China and stimulated me to visit there early in 1980. Fig 2. Initial report of research on antimalarial activity of artemisinin in English During the Vietnamese war of the 1960’s, resistance to the best antimalarial drug available at that time, chloroquine, was becoming increasingly common in the malignant tertian malaria parasite, Plasmodium falciparum . The lives of large numbers of non-immune indigenous people in Southeast Asia, and others such as American soldiers, were being threatened by the lack of an alternative treatment. While their infections could usually be cured by quinine, supposedly the oldest known antimalarial drug, it is a toxic compound obtainable only from trees most of which were grown on plantations in Indonesia, and supplies of it were scarce. In southern China adjacent to North Vietnam, chloroquine resistance was also becoming a threat, and the Chinese Maoist government ordered its scientists to seek an alternative antimalarial to chloroquine with which to treat their own soldiers and the general populace. In this work, the People’s Liberation Army Research Institute joined with scientists of the China Academy of Traditional Chinese Medicine. A Qinghaosu Antimalarial Co-ordinating Group was formed for the project. China has a long and successful tradition of herbal medicine and it was within the old writings on traditional medicinal plants that Chinese scientists began to search for leads. The therapeutic value of the weed popularly called ‘qing hao’, Artemisia annua , had been used for the treatment of such disorders as fevers, diarrhoea and several skin ailments such as boils, and other infectious conditions. Although the nature of the agent causing malaria was, of course, not recognised until the late 19th century, the intermittent fever it produced was well known, and Chinese texts of materia medica, dating from as long ago as the 4th century AD, described the value of concoctions made from qing hao for the relief of such fevers. Fig.3 Fragment of silk manuscript describing anti-fever action of qing hao (circa 340 AD) An active compound subsequently called ‘qinghaosu’, with potent antimalarial properties, was extracted with some difficulty from qing hao. This plant is a widely distributed and common species of wormwood, found in many countries in Asia and Europe. The botanical identity of qing hao was itself the subject of much learned debate, and it is now acknowledged that two different members of the genus Artemisia (Family Asteraciae) contain a chemical, a sesquiterpene lactone that was called originally ‘arteannuin’ (after the Latin name of the plant) and is now known as ‘artemisinin’. Fig.4 First visit of the author to Beijing, February 1980 During my first visit to the China Academy of Traditional Chinese Medicine in Beijing (Fig.4) I was shown a collection of plants derived from seeds of different varieties of Artemisia annua . This plant has spikes of very small, yellow, mimosa-like flowers (Fig.5), and the leaves have a delicate, pleasant, aromatic odour when touched or squeezed. The seeds which are tiny and dust-like, are collected in small paper sachets that are placed around the spikes once the flowers are mature and have been either self-pollinated, or pollinated by visiting insects. From my experience with growing the plant in a closed greenhouse in my home in England, I suspect that self-pollination is a common process for its reproduction. The institute’s scientists discovered that a simple aqueous infusion of the crushed whole plant produced the maximum yield of the compound that was, however, very poorly soluble in water. In mice experimentally infected with malaria, the maximum level of activity of artemisinin, the active extract of ‘qinghao’ (which the Chinese named ‘qinghaosu’ and which we called QHS for short) was obtained by injecting an oily solution of the chemically purified substance. In subsequent clinical trials, an oily solution was also found to give the maximum level of activity in patients naturally infected with malaria. However, having to inject an oily solution is not an ideal way of administering a drug and the Chinese devoted much effort to finding a water-soluble and stable derivative. An early result of this research was the synthesis of artesunate. The action of this analogue of artemisinin in human patients was shown to be very rapid, even against infection with strains of P.falciparum that were highly resistant to chloroquine. Animal experiments confirmed the lack of cross-resistance between the two compounds. Before leaving Beijing, I asked to be taken to visit a typical herbalist store where I hoped to see, and possibly purchase, some dried medicinal plants. In the first and only store I visited, the shop assistant showed me a large drawer and several glass jars containing dried, pleasantly fragrant qing hao of which I purchased a small packet to take home with me (Fig.6). and he readily explained to me, through my host, the wide range of ills for which this plant was a popular remedy. Qing hao has also spread beyond Asia and Europe to other countries with temperate climates. In May 1982 I visited the Walter Reed Army Institute of Research (WRAIR) near Washington to discuss studies I was carrying out in association with their massive antimalarial programme. The conversation naturally turned to qing hao which, by then, was becoming a hot topic among everybody concerned with the search for new antimalarial drugs. It was a pleasantly warm spring day when one of my colleagues took me outside the main building where I saw bunches of a plant spread out on a trestle table to dry in the open air. The plant was qing hao. One of my hosts who was a Boy Scout troop leader in his spare time, was taking his group for an outing along the banks of the nearby Potomac River when he spotted an unusual plant growing in abundance. As a brief inspection told him immediately that this must be none other than Artemisia annua , he and his scouts gathered as much as they could carry of the weed and took it to WRAIR, so that studies could be carried out there to confirm its identity and antimalarial activity. Within days they knew that they had struck gold. How qing hao reached the Potomac River is unknown. It seems more than likely that Chinese immigrants years before had, like me, brought some of their traditional medicine with them, and that seed had accidentally been dispersed and the plant become colonised in that area. The ease with this can happen was something of which I was already acutely aware. Ruth and I in our small conservatory had raised a number of magnificent plants over 1.4 metres tall from the dried qing hao that I had brought back from Beijing. As far as I was aware, A.annua did not occur in England and, not wishing it to run wild around our garden, I had taken the precaution of destroying the plants as soon as I had photographed them. Two years later, in early summer, I spotted growing at the foot of my garage wall a plant about 30 cm high with a familiar leaf. It was qing hao. I searched around to see if I could find any more of the plants but found none, so uprooted the sole plant and transferred it into a small plant pot which I transferred next day to my laboratory where it would be out of harm’s way. I had to be away for some days during which, unfortunately, my staff forgot to water it, and all that remained when I returned was a sad, shrivelled, flowerless weed. The Chinese laboratories were, at that time, very poorly equipped, and the staff were keen to develop a working relationship with appropriate centres in other countries where further studies could be made with the QHS compounds. However, they were also rather wary of the sometimes unscrupulous methods adopted by some sectors of the pharmaceutical industry, and even academic centres, when it came to making use of the products and intellectual rights of individuals and research centres in less well endowed institutes. It was perhaps a little surprising to me when my Chinese hosts expressed their eagerness for one of their research staff to come to work with my team which, by late 1979, I had established at the London School of Hygiene and Tropical Medicine (LSHTM). I was able to organise through the newly formed UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR for short) two fellowships, the first for Li Ze Lin (Fig 7), a biologist from the Department of Pharmacology of the Institute of Chinese Materia Medica in Beijing and, at a later date, another for a biochemist named Gu Hao Ming. He was at the time working in the Shanghai Institute of Materia Medica where I originally encountered him on my second visit there. Fig.7 Dr Li Ze Lin in London, 1980 Ze Lin arrived in London just before Christmas of 1980 and Ruth and I went to meet her at Heathrow airport. We waited for such a long time at the arrivals exit that we feared she had missed the flight. It was, as far as we knew, her first venture outside China although her husband, an oncologist, was already I believe working on a fellowship at the International Cancer Research Centre in Lyon. Finally a very tired and bewildered Chinese lady turned up, and we duly took charge of her, driving her into Bloomsbury where she had been booked into a typical small hotel almost adjacent to the LSHTM. We went in with her to check the accomodation and settle her in, but both of us immediately agreed that no way could we leave this poor stranger alone over the coming holiday period, speaking relatively poor English and knowing nobody in London. We left her there for that first night to get some sleep, then came back the next day and drove her to our home in Hertfordshire where she spent the first couple of weeks of her stay in England. I had experienced for myself the simplicity of life in Beijing, the sad, almost uniform clothing worn by most people, the frugality of their living. Ze Lin could not get over the fact that we had such a thing as running hot water, central heating plus a small wood fire, a good variety of food and drink, and nobody to look over her shoulder. It was a joy to be able to host her. She was anxious to try to do something to help Ruth with domestic matters and Ruth took her under her wing. One day Ruth discovered that Ze Lin had come across a winter pullover that she was knitting for me, and decided that she could contribute to its production. Ze Lin had already added a few rows, albeit it in a somewhat different stitch, but it added a certain charm to the garment which I still wear to this day, a quarter of a century later, when the weather is exceptionally cold. To my pleasant surprise Ze Lin had been permitted by the Ministry of Health of the PRC to bring with her, samples of a number of the best QHS analogues that had been designed in her institute, for us to examine together in my laboratory under the WHO/TDR CHEMAL project with which we were engaged. When Gu subsequently joined us the following year, we were able to extend the range of our research. This was, as far as I know, the first research carried out on QHS and any of its analogues outside China, and the Li-Gu members of my team were among the first Chinese scientists allowed to work outside their home country since the end of Mao’s ‘Cultural Revolution’. In 1985 we published our first paper on a joint study I carried out with my colleagues David Ellis, David Warhurst and George Tovey, together with Ze Lin and Gu, on the changes that QHS produces in malaria parasites as observed with the electron microscope. The following year Ze Lin, David Warhurst, my chief technologist Brian Robinson and I published the results of our studies comparing the action of QHS with four of its analogues, including artesunate, against a large range of malaria parasites of mice, among them strains that were resistant to all currently used and some new antimalarial drugs of different chemical types, thus consolidating our knowledge of the enormous potential of the Chinese compounds. The Chinese government was very concerned that its own research establishments should be acknowledged by the outside world as the discoverers of the antimalarial potential of one of their own traditional remedies. They had already started to manufacture QHS for medicinal use, but recognised that they lacked the levels of expertise to supply a drug that would be acceptable outside China and some other countries of Southeast Asia, because of their lack of knowledge of internationally acceptable production methods and standards. They were anxious to acquire this knowledge and approached WHO for help. Fig.8 Members of CHEMAL team with Chinese colleagues on Great Wall of China, 1981 In October 1981 I was able to set up a joint meeting of the CHEMAL team with the Chinese scientists in Beijing. Included in my team (Fig.8) was the current director of the WRAIR antimalarial programme, Craig Canfield, whose colleagues had acquired considerable experience in the development of novel drugs to the internationally demanded standards of production, in relation to compounds of their own, and who by this time had also gained some experience with some of their own novel derivatives of QHS. Contrary to uninformed rumours that were circulating outside China at that time, our hosts displayed a total frankness as regards their own programme and problems relating to QHS, and those analogues that they themselves were developing. On Craig’s initiative, it was arranged that one of his own staff would be seconded to Beijing to advise the Chinese how to modify their programme in order to manufacture QHS at an internationally acceptable standard. Following this move, production soared ahead at one of the Chinese pharmaceutical factories that, to the present time, supplies a significant part of the global requirements of QHS and several of its analogues, such as artesunate. The late 1970’s saw the beginning of an epoch during which interest was being stirred in the pharmaceutical industry outside China in the commercial and practical potential of novel compounds, either derived from QHS, or based on the chemical structure of these compounds. Both through my role in the CHEMAL research programme and my association with several individual pharmaceutical companies, with WRAIR and individual chemists from industry and academia, my small team, working on a shoestring budget, became a focus for the primary screening in mice infected with rodent malarias, which is one of the basic steps in antimalarial drug development. Meanwhile in 1981 I and my colleagues reported that it was relatively easy to select strains of mouse malaria that were resistant to QHS. From 1987, with my colleague David Warhurst and a Zimbabwean PhD student named Arthur Chawira we were able to demonstrate that by combining QHS with a number of synthetic antimalarial drugs with different structures and modes of action, the activity of QHS could be enhanced. The search for further novel compounds with a similar mode of action to QHS was taken up in a number of research centres outside China. For example, during the early 1990’s I had encountered an English chemist named Charles Jefford, working in the University of Geneva, who was one of the first to explore the mode of action of compounds with structures similar to that of QHS. For several years we enjoyed an interesting and productive collaboration that led, in time, to his synthesis of a very promising compound, somewhat related to QHS. We hoped that it would be adopted by a pharmaceutical company with the means to carry out the very costly developmental steps that any new medication must undergo up to and, hopefully, during clinical investigation. Not surprisingly, he was not the only chemist to take up the challenge, and I was fortunate to be involved over the years with others, including Gary Posner and Richard Haynes, who also succeeded in producing highly promising lead compounds.. It is extremely difficult to overcome all the hurdles involved in new drug development, and sad that Jefford’s most promising candidate compound never reached the stage of clinical trial. However, that to date has been the fate of all the others and, even at the time of writing in 2009, no other truly novel compound of the QHS or similar chemical type has found its way into clinical trial. In parallel with our initial collaborative studies with our Chinese colleagues I was able to pursue my own speciality which was to explore the potential value of drug combinations as opposed to monotherapy. The main thrust of the final stages of my research programme prior to my retirement, continued to be the study, in my rodent malaria models, of carefully selected drug combinations for their ability to impede or prevent the selection of drug resistance. To do this we had first to confirm how readily malaria parasites could become resistant to the QHS type of compound. In our later experiments it turned out that parasites could become resistant to such compounds, although at a much slower rate than we were accustomed to see with any other type of antimalarial drug. But become resistant the parasites did, given enough time. Having established that, we next needed to see whether we could influence this process by combining one or other of them with drugs of a different structural type. We had already produced a wealth of interesting data with other combinations not including QHS, some of which were very effective in slowing down the selection of resistance to the individual components, and we were finally able to produce data showing that this should be possible with combinations of a QHS-type compound with a compound of a different chemical type, for example a relatively new type of antimalarial called mefloquine. I was agreeably surprised to read in 2004 a paper by two staff members of WHO the gratifying acknowledgement that, “The idea that drug combinations could be used to delay antimalarial drug resistance came from Peters.” The accompanying reference was to a paper I had published in 1980 in which I suggested that artemisinin would form a promising component for this purpose. From about 2006 this policy came to be referred to as ‘Artemisinin combination therapy’ (ACT). The concept of administering QHS-type compounds, especially artesunate, in combination with other antimalarials, mefloquine being one of the first examples, came to be explored in the clinic, partly under the guidance of CHEMAL. Prominent among the groups carrying out this work outside China was a joint Thai-British team supported by the UK Wellcome Trust and Oxford University. Led by experienced clinical staff of Mahidol University in Bangkok in close collaboration with Nicholas White and his Oxford colleagues, clinical trials were established in naturally infected patients in several centres, notably Bangkok, and Cheng Mai on the Thai-Burmese border. White also made a ground-breaking mathematical analysis of the likely effects of artemisinins, alone or in combination with a partner compound such as mefloquine, on the rate of cure and/or recrudescence of malaria infection. Unfortunately that particular combination was at risk of failing as there already existed an underlying high level of resistance to mefloquine in Thailand, a factor to which inadequate attention was paid at the time. In 2005 in one of my last papers, (Part LXIII of a series we published in the Annals of Tropical Medicine and Parasitology from 1968 onwards), we described the potential value of a combination of three compounds that was launched into clinical trial in East Africa by the pharmaceutical company GlaxoSmithKline, but which had, unfortunately, to be withdrawn due to toxicity caused by one of the components in a small number of individuals. Paradoxically it was an old compound called dapsone that was one of the first drugs used to cure leprosy and that continues to be used for that purpose to this day as a major component of a combination of antibacterial compounds termed Multi-Drug Therapy (MDT). At the time of writing, another ACT is starting to undergo studies in malaria-infected patients. Early on in my collaborative work with Chinese chemists, I had received from them a sample of a very active new compound called pyronaridine. They themselves had issued promising reports on its action, alone or with artesunate, against chloroquine-resistant P.falciparum malaria in Chinese patients. In a paper we published in 2000, (Part LVIII in our series), we first recommended the use of this combination. Prior to its publication, I had presented data on this and the Chinese work at a special meeting held by WHO in Geneva late in the 1990’s. I strongly promoted the idea of testing a pyronaridine-artesunate combination in advanced stages of drug development that would have to precede its possible investigation in human subjects. It is a reflection of both the politics and cost of drug development that only a decade later is this combination, now known under the name of Pyramax, in clinical trial. It soon became evident that a shortage of QHS compounds and the high cost of their production would become serious obstacles to their deployment, especially if they were to be administered in combination with a partner compound. On the basis largely of the success of the clinical studies in Thailand, the principle of deploying QHS with a second drug became generally accepted and, in 2006, the use of an ACT was officially promoted at the international level. There remained, however, the problems of how to produce enough of the parent plant, A.annua and how to do so at a cost that would be affordable in the most needy, but often impoverished countries. The mass cultivation of A.annua was extended not only within Southeast Asia, but also in such areas as the relatively temperate highland areas of East Africa where large plantations and extraction plants were organised, with support from international funds. Still the final product is costly and means continue to be sought to produce QHS at a significantly lower price. International awareness of the grinding burden of malaria, especially on the African continent, has finally led to massive inpouring of money on an unprecedented scale from philanthropic individuals and organisations, such as the Gates Foundation which, by 2008, had provided for malaria research and control the previously unthinkable sum of $1.2 billion dollars to underpin plans not to ‘eradicate’ but to ‘eliminate’ malaria. This new target was proposed by the UN Secretary General in a speech given on World Health Day in April 2008. Plant geneticists and molecular biologists were enrolled in the search for novel means of production, one of these being the ingenious transfer of the genes within A.annua that are responsible for the plant’s synthesis of QHS, into yeasts that can be cultured en masse in fermentation chambers by techniques long ago developed for the mass production of such compounds as penicillin (and beer!). One of the most recent and ingenious avenues being explored is the modification of a biochemical pathway in chicory, a widely cultivated vegetable, so that it synthesises a natural precursor of QHS which can be readily and cheaply extracted for simple chemical modification into QHS itself. Meanwhile my forebodings of the exceptional ability of malaria parasites to produce drug-resistant mutants, even when appropriate combinations are used (which is by no means always the case) or correct doses are given, seem to be justified with some of the first indications of the emergence of resistance to certain ACT combinations in that epicentre of drug resistance, the Thai – Cambodia border region. It is my hope that the Pyramax combination might just arrive in time to extend the future of ACT combinations, which will no doubt include some quite novel QHS derivatives, or other compounds with a similar mode of action. Only time will tell. In the meantime one must hope that the huge burden of malaria will be reduced by applying, in addition, quite other means for controlling malaria transmission, such as mass protection by insecticide – treated mosquito nets, and the judicious reintroduction of DDT to destroy the mosquito vectors that enter dwellings. Moreover, good progress at last is being made on the development of an antimalarial vaccine for use in young children, although the mass deployment of such a prophylactic measure itself must be approached with caution for a variety of practical logistic and other reasons including the ease with which malaria parasites may modify their genetic structure. Fortunately there is hope that artesunate itself (or an analogous compound) may have an alternative and exciting future over and beyond its deployment against malaria. In the first place this compound has been found to be effective in the treatment of several other parasites that afflict humans, the worm infection known as schistosomiasis, for example. Of overall importance, artesunate has been reported recently by investigators in China and elsewhere, to possess remarkable activity against certain types of tumour, both in the laboratory and in a number of human patients suffering from advanced cancer of widely differing types. The ability to administer a well-tolerated compound such as artesunate, especially if it can be shown to exhibit enhanced activity with a second equally safe partner drug, would have an enormous potential value in cancer therapy compared with regimens of currently used drugs and of radiotherapy that are frequently poorly tolerated. Very sadly, several of my colleagues and I had been so focussed for years on the antimalarial action of artesunate, that we only recently learned of its anticancer potential. Meanwhile, the spouses of five of us have succumbed to cancer. Included was my own wife, Ruth, who died from the devastating effects of a malignant tumour at the end of 2007. http://peters.aegauthorblogs.com/2010/11/08/conversations-with-myself-8th-november-2010/
标签: 衍生物
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