David J. Newman

Natural Products as Leads to Potential Drugs: An Old Process or the New Hope for Drug Discovery?

From approximately the early 1980s, the “influence of natural products” upon drug discovery in all therapeutic areas apparently has been on the wane because of the advent of combinatorial chemistry technology and the “associated expectation” that these techniques would be the future source of massive numbers of novel skeletons and drug leads/new chemical entities (NCE) where the intellectual property aspects would be very simple. As a result, natural product work in the pharmaceutical industry, except for less than a handful of large pharmaceutical companies, effectively ceased from the end of the 1980s. What has now transpired (cf. evidence shown in Newman and Cragg, 2007 and Figures 1 and 2 below showing the continued influence of natural products as leads to or sources of drugs over the past 26 years (1981–2006)) is that, to date, there has only been one de novo combinatorial NCE approved anywhere in the world by the U.S. Food and Drug Administration (FDA) or its equivalent in other nations for any human disease, and that is the kinase inhibitor sorafenib (1, Chart 1), which was approved by the FDA in late 2005 for renal carcinoma. However, the techniques of combinatorial chemistry have revolutionized the deVelopment of active chemical leads where currently, instead of medicinal chemists making derivatives from scratch, a procedure is used whereby syntheses are based on combinatorial processes so that modifications can be made in an iterative fashion. An example of such a process would be the methods underlying the ultimate synthesis of the antibiotic linezolid (Zyvox, 2) by the Pharmacia (now Pfizer) chemists starting from the base molecules developed in the late 1980s by DuPont Pharmaceutical, who reported the underlying antibiotic activity and mechanism of action of this novel class of molecules, the oxazolidinones.

cAMP-phosphodiesterase inhibitors and tracheal smooth muscle relaxation

Abstract A series of compounds drawn from a wide variety of chemical and pharmacologic classes were tested for their ability to act as inhibitors of a guinea pig tracheal cAMP-phosphodiesterase. Active compounds, defined as equal to or more potent than 1,3-dimethylxanthine (theophylline), were subsequently tested for guinea pig tracheal smooth muscle relaxant activity in vitro . A strong correlation ( r = 0.988 with 95 per cent confidence limits of 0.933 to 0.988) was found between the two activities, suggesting that, under these conditions, smooth muscle relaxation was due to elevation of tracheal cAMP levels.

Actinomycin D inactivating enzymes fromActinoplanes missouriensis and several other members of theActinoplanaceae family

SummaryThe enzymes for inactivating actinomycin D appear to be widely distributed amongst species belonging to the familyActinoplanaceae. Actinomycin D was completely or partially inactivated by cell-free extracts fromActinoplanes missouriensis, Streptosporangium viridogriseum, S. violaceocbromogenes, S. roseum, S. brasiliense, S. albidum, Spirillospora sp.,Sp. albida, Kitasatoa kauaiensis, Planobispora longispora, P. rosea, Dactylosporangium aurantiacum, andD. thailandense. No inactivation was obtained with extracts fromAmorphosphorangium auranticolor, Ampullariella lobata, Planomonospora parontospora, andP. venezuelensis. Actinomycin lactonase was partially purified by ultracentrifugation, ultrafiltration, and isoelectric focusing from noninduced cells ofActinoplanes missouriensis. The enzyme has a molecular weight of greater than 200,000 daltons and an isoelectric point of 4.3 to 4.4.

A tribute to the late Emeritus Professor Lester A Mitscher

It is a definite honor and a privilege to be asked to pay a tribute to the late Emeritus Professor Lester A Mitscher. In contrast to my fellow editorial writers (Drs James McAlpine and Gordon Cragg), my emphasis will be more on the impact that Professor Mitscher had upon the education of medicinal chemists world-wide, and I will finish with a comment on what some of his earlier work at Lederle Laboratories led to in the tetracycline field. In 1995, in conjunction with Sir Robin Ganellin (the co-inventor of the first billion-dollar drug, cimetidine) and Professor John Topliss, he investigated the apparent anomaly that pharmaceutical companies, world-wide, tended to hire organic chemists rather than PhD graduates in medicinal chemistry. On investigation, it turned out that medicinal chemistry was effectively a discipline within Schools of Pharmacy, not in Schools of Chemistry. Thus, newly hired organic chemists in pharmaceutical companies had to effectively ‘learn on the job’ in contrast to graduates from medicinal chemistry departments in Schools of Pharmacy. A review article in 1998 by the same authors, further extended their earlier results and had within the body of the document, that pharmaceutical houses, particularly in the US, had little regard for chemists with formal academic training in organic chemistry and with substantial training in biological topics. Then in 2000, a much more complex analysis covering eight major countries with schools of medicinal chemistry (all in Pharmacy Schools) demonstrated that the earlier findings were replicated but with inter-country variations. From these findings, Professor Mitscher and his colleagues were able to influence the curricula that medicinal chemists would be using. It is a pity that a similar analysis has not been done in the last 16 years, as today, drug discovery requires that organic chemists need a very good background in biological areas (which medicinal chemists in Schools of Pharmacy have), to design molecules that have ‘drug-like properties’. It is apparent that Professor Mitscher and his colleagues were well ahead of their time in their analyses. In the late 1980s I was at Lederle Laboratories working in their antibiotic discovery program, and knew the chemists that were involved in the synthesis and discovery of what became ‘tigecycline’. The organic chemists involved realized that the basis for their work was the earlier discoveries made by Professor Mitscher during his time at Lederle, and they also realized that the materials which they synthesized had to be biologically relevant, otherwise all that they would have been doing would have been some elegant synthetic work around a natural product backbone. Some of the chemists involved had been recruited as synthetic chemists but others had significant biological training in their backgrounds, and they worked ‘hand-in-glove’ with microbiologists in their discovery and then subsequent development of these agents. If one then does a literature search as I did using the Scopus database, the breadth of Professor Mitscher’s interests and the vast number of world-wide scientists that cited his work became apparent. The scientific world lost a major influence for medicinal chemistry, particularly based on natural products, on his death, but he was able to pass on his love of medicinal chemistry and natural products as leads, to many current groups, so his influence will continue.

A simple technique for determination of P50 values of blood and erythrocytes

Abstract A simple, rapid, and repetitive technique for determining the P 50 value of blood or erythrocyte suspension is described. The system allows comparative values of various blood samples or treatments to be obtained under the same gassing and equilibration conditions. For a series of normal human erythrocytes in physiologic buffer ( n = 37), P 50 = 27.45 ± 1.34 mm and on sextuple analyses of one sample, P 50 = 28.40 ± 0.50 mm. A computer program is given that converts raw data to P 50 values at pH 7.40.