Samuel J. Danishefsky

Bio: Samuel J. Danishefsky is an academic researcher from Memorial Sloan Kettering Cancer Center. The author has contributed to research in topics: Total synthesis & Glycal. The author has an hindex of 72, co-authored 533 publications receiving 19492 citations. Previous affiliations of Samuel J. Danishefsky include Harvard University & University of Pittsburgh.

The B-alkyl Suzuki-Miyaura cross-coupling reaction: Development, mechanistic study, and applications in natural product synthesis

Abstract: The development of new reactions that facilitate the creative and efficient synthesis of molecular structures with desirable properties continues to fascinate chemists. The test of a significant contribution is its acceptance over time by the scientific community. The B-alkyl Suzuki-Miyaura cross-coupling reaction appears to be one such reaction. Since its disclosure by Suzuki and Miyaura in 1986, this reaction has been an attractive solution to challenging synthetic problems.

Glycals in Organic Synthesis: The Evolution of Comprehensive Strategies for the Assembly of Oligosaccharides and Glycoconjugates of Biological Consequence

Abstract: This review provides a personal account of the explorations of a research group in oligosaccharide and glycoconjugate construction. The journey began twenty years ago with the study of Diels–Alder reactions of complex dienes. By extending this methodology to aldehydo-type heterodienophile equivalents, access to unnatural glycals was gained (LACDAC reaction). From this point a broad-ranging investigation of the use of glycals in the synthesis of oligosaccharides and other glycoconjugates was begun. Mobilization of glycals both as glycosyl donors and glycosyl acceptors led to the strategy of glycal assembly. Several new glycosylation techniques were developed to provide practical underpinning for this logic of glycal assembly. Glycal-based paradigms have been shown to be nicely adaptable to solid phase supported synthesis. Moreover, glycal assembly—both in solution and on solid phases—has been used to gain relatively concise and efficient entry to a variety of biologically interesting and potentially valuable constructs. Some of these syntheses, particularly in the field of tumor antigens, have led to novel compounds which are in the final stages of preclinical assessment. This review presents an account of the chemical reasoning at the center of the program.

Gelsemine: a thought-provoking target for total synthesis.

Abstract: Gelsemine and 21-oxogelsemine have been synthesized through several routes. This Review focuses on the comparison of the different strategies to assemble the bicyclo[3.2.1]octane core, to introduce the bridgehead quaternary C20 to form the pyrrolidine moiety, to construct the oxindole residue, and to close the tetrahydropyran ring en route to gelsemine.

Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method

Abstract: This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively.

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Abstract: This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74...

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Abstract: The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

Abstract: A. Water Exchange 2326 B. Proton Exchange 2327 C. Electronic Relaxation 2327 D. Relaxivity 2331 E. Outerand Second-Sphere Relaxivity 2334 F. Methods of Improving Relaxivity 2336 V. Macromolecular Conjugates 2336 A. Introduction 2336 B. General Conjugation Methods 2336 C. Synthetic Linear Polymers 2336 D. Synthetic Dendrimer-Based Agents 2338 E. Naturally Occurring Polymers (Proteins, Polysaccharides, and Nucleic Acids) 2339