Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.

Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4-degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1.

Streamlined Symmetrical Total Synthesis of Disorazole B1 and Design, Synthesis, and Biological Investigation of Disorazole Analogues.

Taking advantage of the C2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B1, whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure-activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin.

Herein, we describe a biomimetic entry to (+)-3-hydroxymethylartemisinin (2) as well as to the artemisinin derivatives (+)-3-hydroxymethyl-9-desmethylartemisinin (16) and (+)-3-hydroxymethyl-9-epi-artemisinin (18), starting from the known and readily available chiral aldehyde 3 and alkyne 4. Subsequently, the synthesized compounds have been evaluated for their antimalarial activity against the drug-sensitive P. falciparum NF54 strain. All of them were inactive. In addition, they did not show any toxicity against L6 cells (a primary cell line derived from rat skeletal myoblasts). These results contribute to a better understanding of artemisinins mechanism of action.

Syntheses of Cyclopropyl Analogues of Disorazoles A1 and B1 and Their Thiazole Counterparts.

Modular syntheses of disorazoles A1 and B1 analogues in which the epoxide moieties of the natural products were replaced with cyclopropyl units have been achieved. Targeted as part of a structure-activity relationships study, these syntheses were successfully extended to the thiazole counterparts of these analogues. The retrosynthetically defined fragments were assembled through Yamaguchi esterification, Cu/Pd-catalyzed cross-coupling, Yamaguchi macrolactonization, and Cu-catalyzed cross-coupling as the key reactions. Further synthetic and biological investigations of such analogues are expected to lead to the discovery and development of potential payloads for antibody-drug conjugates as targeted cancer therapies.

Total Synthesis and Biological Investigation of (-)-Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific.

Here, we describe an efficient and diversity-oriented entry to both (-)-artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin.

Lewis Acid Mediated Nazarov Cyclization as a Convergent and Enantioselective Entry to C-nor-D-homo-Steroids.

A straightforward synthesis of C-nor-D-homo steroids starting from (+)-Wieland-Miescher ketone is reported. This convergent synthetic strategy utilizes a scalable diastereoselective Nazarov cyclization of functionalized chiral aryl vinyl ketones, allowing for further functionalization. The ability to conduct this key transformation on a multi-gram scale paves the way for the synthesis of a variety of completely new C-nor-D-homo steroids, without the need of a classic steran steroid rearrangement or achiral linear reaction sequences.