Preparation and Activities of Macromolecule Conjugates of the CCR5 Antagonist Maraviroc

CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and <i>Staphylococcus aureus</i> infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides

Formylbenzene Diazonium Hexafluorophosphate Reagent for Tyrosine-Selective Modification of Proteins and the Introduction of a Bioorthogonal Aldehyde

4-Formylbenzene diazonium hexafluoro<u>p</u>hosphate (FBDP) is a novel bench-stable crystalline diazonium salt that reacts selectively with tyrosine to install a bioorthogonal aldehyde functionality. Model studies with <i>N</i>-acyl-tyrosine methylamide allowed us to identify conditions optimal for tyrosine ligation reactions with small peptides and proteins. FBDP-based conjugation was used for the facile introduction of small molecule tags, poly­(ethylene glycol) chains (PEGylation), and functional small molecules onto model proteins and to label the surface of living cells

12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess–Kürti–Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (<i>E</i>) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner–Wadsworth–Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications

12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents

The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess–Kürti–Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (<i>E</i>) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner–Wadsworth–Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications

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

Streamlined Total Synthesis of Trioxa­carcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxa­carcin Analogues

A streamlined total synthesis of the naturally occurring antitumor agents trioxa­carcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthra­quinones and chloro anthra­quinones from simple ketone precursors and phenyl­selenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody–drug conjugates