Does merger & acquisition (M&A) strategy matter? A contingency perspective

This paper takes a contingency approach to investigate whether there are market performance variations for different types of M&A. Eight different types of M&A are identified in a typology based upon the conjunction of three contextual dimensions: external environmental, acquiring firm level strategy and CEO motivation. Drawing upon a sample of 1,926 domestic UK deals we evaluate the typology to determine whether the financial markets distinguish between different types of M&A. Results indicate significant market and risk-adjusted performance differences by M&A type. These confirm that a contingency approach to M&A performance has merit. We suggest that the proposed integrated typology, that recognizes the importance of multiple aspects of strategic fit to M&A performance, addresses the paradox that M&A practitioners continue to pursue deals despite widespread acceptance that they result in high failure rates

Novel copper(II) complex of N-propyl-norfloxacin and 1,10-phenanthroline with enhanced antileukemic and DNA nuclease activities

We have synthesized and characterized a novel copper(II) complex of the fluoroquinolone antibacterial drug N-propyl-norfloxacin (Hpr-norf) in the presence of 1,10-phenanthroline (Phen) and studied its biological properties as antitumor antibiotic and antimicrobial agent. Human acute myeloid leukemia cell line HL-60, MTT assay, and Trypan blue assay were used to test the antileukemic, the cell viability, and the structural integrity of the cell membrane and cell proliferation properties of (chloro)(Phen)(N-propyl-norfloxacinato) copper(II) (complex 1), respectively. We found that the proliferation rate and viability of HL-60 cells decreased after treatment with complex 1, leading to cell death through apoptosis in a time-dependent manner. The antimicrobial activity of complex 1 has been tested, revealing an increased potency in comparison to the free Hpr-norf. Complex 1 proved to be capable of acting as an independent nuclease by inducing nicking of supercoiled pUC19 plasmid. Our results suggest that 1 may provide a valuable tool in cancer chemotherapy. © 2008 American Chemical Society

Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries

Isolated from certain species of soft corals, the sarcodictyins, eleutherobin, and eleuthosides have become important synthetic targets due the their novel molecular architectures, important biological activities, and potential in medicine. Of particular interest is their Taxol-like mechanism of action involving disturbance of the tubulin−microtubule interplay resulting in tumor cell death. Their scarcity and biological profile prompted us to initiate a program directed at exploring their chemical synthesis and chemical biology. Herein we report (a) the first total synthesis of sarcodictyins A (7) and B (8) by a combination of solution and solid-phase methods through the attachment of the common precursors 18 or 20 on solid support, thus generating conjugates 23 and 24, followed by standard chemical manipulations; (b) the construction of a combinatorial library of sarcodictyins by solution and solid-phase chemistry modifying the C-8 ester, C-15 ester, and C-4 ketal functionalities, and, therefore, producing analogues of the general structures 33, 37, and 40; (c) the tubulin polymerization properties of all members of the library; and (d) the cytotoxic actions of a selected number of these compounds against a number of tumor cells including Taxol-resistant lines. Several of the synthesized analogues were identified to be of equal or superior biological activities (e.g. 60, 61, 63, 66−70, 73, 76, 85, 92) as compared to the natural products, setting the stage for further developments in the field of cancer chemotherapy

Preparation of sarcodictyin and eleutherobin and analogs useful for stabilizing microtubules

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Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody–Drug Conjugates

Improved, streamlined total syntheses of natural tubulysins such as V (<b>Tb45</b>) and U (<b>Tb46</b>) and pretubulysin D (<b>PTb-D43</b>), and their application to the synthesis of designed tubulysin analogues (<b>Tb44</b>, <b>PTb-D42</b>, <b>PTb-D47</b>–<b>PTb-D49</b>, and <b>Tb50</b>–<b>Tb120</b>), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., <b>Tb111</b>: IC₅₀ = 40 pM against MES SA (uterine sarcoma) cell line; IC₅₀ = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC₅₀ = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure–activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies

Total Synthesis and Biological Evaluation of Natural and Designed Tubulysins

A streamlined total synthesis of <i>N</i>¹⁴-desacetoxytubulysin H (<b>Tb1</b>) based on a C–H activation strategy and a short total synthesis of pretubulysin D (<b>PTb-D43</b>) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (<b>Tb2</b>–<b>Tb41</b> and <b>PTb-D42</b>) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., <b>Tb14</b>), some with exceptional potencies against certain cell lines [e.g., <b>Tb32</b> with IC₅₀ = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure–activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies