[Tautomerism of purine and pyrimidyne bases]. / Tautomeria zasad purynowych i pirymidynowych.

In this paper, I am presenting the background and a short outline of the research on the neutral and ionic tautomeric forms of pyrimidines, purines and their derivatives, carried out in the late 1960s under the guidance of professor David Shugar, in the Biophysics Department of Warsaw University.

Translation of the Philadelphia chromosome into therapy for CML.

Throughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy. These range from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease. The successful development of imatinib as a therapeutic agent for CML can be attributed directly to decades of scientific discoveries. These discoveries determined that the BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib, with imatinib significantly improving the long-term survival of patients with CML. Continuing in this tradition of scientific discoveries leading to improved therapies, the understanding of resistance to imatinib has rapidly led to strategies to circumvent resistance. Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers.

Forty years of antipsychotic Drug research--from haloperidol to paliperidone--with Dr. Paul Janssen.

The authors describe 40 years of antipsychotic drug research with Dr. Paul Janssen, which they have witnessed for a large part from first hand experience. The article describes the start of the Janssen Research and its early successes with antispasmodics and analgesics. The discovery of haloperidol followed from a serendipitous transition from analgesics to antipsychotics and culminated with the historical International Symposium on Haloperidol that was held in Beerse (Belgium) in 1959. The concept of the central role of dopamine receptor binding in schizophrenia has played a decisive part in focusing the Janssen Research on antipsychotics. Paul Janssen did not rest with haloperidol (CAS 52-68-8), but expanded it into the family of butyrophenone antipsychotics, using Haase's handwriting test to clinically characterize the analogues. The emerging significance of serotonin antagonism in schizophrenia is discussed in the light of the discovery of pipamperone (CAS 1893-33-0), a forerunner of the modern so-called atypical neuroleptics. Continued research produced a novel chemical family of neuroleptics, exemplified by pimozide (CAS 2062-78-4) and fluspirilene (CAS 1841-19-6), and yielded selective serotonin 5HT2-antagonists. This research ultimately led to the discovery of risperidone (CAS 106266-06-2) and paliperidone (CAS 144598-75-4), compounds with inbuilt dopamine and serotonin antagonism. The authors discuss the lack of inhibition as a common trait of stereotyped behaviour in schizophrenia and the means of determining it by means of a computerized version of Bente's button press test. Finally the appropriate use of antipsychotics for optimal therapeutic result with minimal side effects is advocated.

Treatment for chronic myelogenous leukemia: the long road to imatinib.

The scientists of today have become accustomed to the extremely rapid pace of progress in the biomedical sciences spurred on by the discovery of recombinant DNA and the advent of automated DNA sequencing and PCR, with progress usually being measured in months or years at most. What is often forgotten, however, are the many prior advances that were needed to reach our present state of knowledge. Here I illustrate this by discussing the scientific discoveries made over the course of the past century and a half that ultimately led to the recent successful development of drugs, particularly imatinib mesylate, to treat chronic myelogenous leukemia.

Role of allogeneic stem cell transplantation for adult chronic myeloid leukemia in the imatinib era.

Due to superior survival in the short to medium term, the first-generation ABL kinase inhibitor imatinib mesylate has generally supplanted all other therapies as the initial treatment of choice in chronic phase chronic myeloid leukemia. The role of allogeneic stem cell transplantation (alloSCT) has shifted from a preferred first-line therapy to a possible second- or third-line therapy. However, despite generally excellent responses to imatinib, some patients respond poorly or lose response, and the risk-benefit equation in these cases may rapidly shift in favor of the alloSCT option. These patients need to be identified as soon as possible so that the alloSCT option can be applied while they are still in controlled chronic phase. Monitoring of imatinib response in patients who have suitable donors and are potentially eligible for alloSCT needs to be frequent, sensitive, and accurate. Clear criteria for switching from imatinib therapy to the alloSCT option should be established for each patient according to the specific risk profile of the transplant. The potential efficacy and safety of clinical trials combining reduced intensity alloSCT with ABL kinase inhibitor therapy warrants further consideration.

The sulfonamide-diaminopyrimidine story.

This paper is devoted to chemotherapy in the sense that Paul Ehrlich (Nobel Prize winner in 1908) coined the word: to describe the cure of infectious diseases by chemical agents without injury to the organism infected. This approach, essentially that of selective toxicity, is applicable to the investigations performed by Gerhard Domagk (Nobel Prize winner in 1939), which resulted in the development of Prontosil rubrum. This agent was active in vivo but not in vitro. Tréfouël supposed that the in vivo action was due to a metabolite of the drug (sulfanilamide), a hypothesis later proved by Fuller in 1937. Sulfanilamide was a simple agent, easy to manufacture and free of patent rights. Thus, more than 5400 derivatives were synthesized and studied in the decades that followed. Research on the side-effects of sulfonamides resulted in the development of diuretics and antidiabetogenic agents. The resurgence of interest in sulfonamides in following years has been associated with the development of diaminopyrimidines by Hitchings (Nobel Prize winner in 1988). It soon became evident that combinations of these drugs produced potent synergistic effects. Trimethoprim, a potent antibacterial agent of this series, was selected for combining with sulfonamides such as sulfadiazine. This line is still continued and even recently new diaminopyrimidine derivatives such as aditoprim and baquiloprim have been synthesized having superior properties in farm animal species. Thus, even nowadays the principles of Ehrlich continue to have a major impact on the development of new veterinary drugs.

History and future of antimicrobial diaminopyrimidines.

Numerous pyrimidine and purine analogs were synthesized in the late forties in G.H. Hitchings' group as potential nucleic acid antagonists. Several key observations finally led to the selection of pyrimethamine as an antimalarial and trimethoprim (TMP) as an antibacterial agent: i) 2,4-diamino-5-substituted pyrimidines interfered with folic acid utilization rather than being thymine antagonists as expected; ii) a large degree of selectivity could be obtained by suitable substitution and non-toxic diaminopyrimidines with preferential antimicrobial activity were found; iii) the identification of dihydrofolate reductase (DHFR) as the specific target for aminopterin and methotrexate in 1958 and for TMP in 1965, and the diversity of this enzyme in different species. Although several diaminopyrimidines were initially tested as monotherapies in clinical trials, the pronounced synergism between some of these new compounds and sulfonamides seen against Plasmodium was finally also applied in the development of TMP. Its combination with sulfamethoxazole later proved one of the most successful agents ever developed. Further milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimoprim, which proved clinically efficacious and safe with once-daily low dose monotherapy. Efforts to discover new antimicrobial DHFR inhibitors have recently intensified. DHFRs from important gram-positive problem organisms such as S. aureus, S. epidermidis have been cloned and sequenced, as well as DHFRs from opportunistic pathogens such as P. carinii, T. gondii, and of mycobacteria. DHFR crystal structures from several of these organisms are available to aid rational inhibitor design.(ABSTRACT TRUNCATED AT 250 WORDS)

Azapirones: history of development.

The azapirones, a unique pharmacologic class that includes buspirone and gepirone appear to offer the promise of both antidepressant and anxiolytic activity. Their singular affinity for the serotonin (5-hydroxytryptamine [5-HT]) type 1A (5-HT1A) receptor subtype may be the factor responsible for the therapeutic activity of these agents. It is hoped that the distinctive characteristics of this new class of drugs will lead to effective therapy for the treatment of mood disorders without the adverse or ancillary effects associated with currently available agents such as the benzodiazepines. The development of drugs for the treatment of anxiety has gradually evolved from less selective agents, such as alcohol, opiates, and the bromides, to progressively more specific drugs, leading ultimately to the development of the benzodiazepine anxiolytics in 1959. The approval of the azapirone buspirone in 1986 marked a new era of psychotherapeutic drug therapy. There is now evidence that this new generation of anxiolytic drugs may offer antidepressant potential in addition to its anxiolytic properties.

Antiplasmodial efficacy of 2,4--diaminopyrimidine0sylfonamide combinations, especially against chloroquine-resistant malaria.

This presentation deals with the historical development of the antifolate pyrimidines and related compounds, first as antimalarial substances and later as potent antibacterial agents. It describes the first quantitation of the combined action, through sequential blockade, of the substances with sulfonamides, and outlines the usefulness of the combinations in the therapy of normally sensitive and multiresistant strains of Plasmodium falciparum.