Chromatin Regulates Genome Targeting with Cisplatin.

Cisplatin derivatives can form various types of DNA lesions (DNA-Pt) and trigger pleiotropic DNA damage responses. Here, we report a strategy to visualize DNA-Pt with high resolution, taking advantage of a novel azide-containing derivative of cisplatin we named APPA, a cellular pre-extraction protocol and the labeling of DNA-Pt by means of click chemistry in cells. Our investigation revealed that pretreating cells with the histone deacetylase (HDAC) inhibitor SAHA led to detectable clusters of DNA-Pt that colocalized with the ubiquitin ligase RAD18 and the replication protein PCNA. Consistent with activation of translesion synthesis (TLS) under these conditions, SAHA and cisplatin cotreatment promoted focal accumulation of the low-fidelity polymerase Polη that also colocalized with PCNA. Remarkably, these cotreatments synergistically triggered mono-ubiquitination of PCNA and apoptosis in a RAD18-dependent manner. Our data provide evidence for a role of chromatin in regulating genome targeting with cisplatin derivatives and associated cellular responses.

Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules.

The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way toward studying isoform-specific cellular processes by means of small molecule intervention.

Directed studies towards the total synthesis of (+)-13-deoxytedanolide: simple and convenient synthesis of the C8-C16 fragment.

A straightforward synthesis of the enantioenriched C8-C16 south part of (+)-13-deoxytedanolide has been reported. The strength of this approach relies on the preparation of similar functionalized fragments via the transformation of a unique dihydrofuran building block through a 1,2-metallate rearrangement.

Collective domino approach toward the core of molecules isolated from the genus Schisandra.

A concise route to the ABC and ABCD core of molecules isolated from the genus Schisandra has been accomplished. The synthesis demonstrated high atom efficiency employing a new one-pot cascade which sequentially built three rings and a quaternary spirocenter.

Construction of spirolactones with concomitant formation of the fused quaternary centre--application to the synthesis of natural products.

Polycyclic structures fused at a central carbon are of great interest due to their appealing conformational features and their structural implications in biological systems. Although progress in the development of synthetic methodologies towards such structures has been impressive, the stereoselective construction of such quaternary stereocentres remains a significant challenge in the total synthesis of natural products. This review highlights the progress in the formation of 1-oxaspiro[4.n]alkan-2-ones (2≤n≤7) with concomitant formation of the quaternary spiro centre.