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Relevant academic research and scientific papers

TREX1 INHIBITORS AND USES THEREOF

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for inhibiting three prime repair exonuclease 1 ("TREX1").

Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents

A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase with an EC50 of 2.7 μM in the MCF-7 breast-cancer cell line, a 7-fold increase compared with that of noscapine (5). This molecule had similar activity (EC50 of 2.5 μM) against the resistant NCI/AdrRES cell line, demonstrating its potential to overcome or avert known resistance mechanisms, unlike current cytotoxic agents. Compound 18g was found to modify the drug-efflux activity of P-gp and, in combination studies, potentiate the antiproliferative activity of vinblastine. These results provide insights into structural modifications to noscapine that will guide future development toward more potent cytotoxic agents that are active against resistant cancer cells.

Total synthesis of graphislactones A, C, D, and H, of ulocladol, and of the originally proposed and revised structures of graphislactones e and F

Graphislactones A-H and the structurally related ulocladol are highly oxygenated resorcylic lactones produced by lichens and fungi. We present total syntheses of graphislactones A, C-F, H and of ulocladol. Graphislactones E, F, and H were synthesized for the first time. The spectra of graphislactones E and F synthesized as the originally proposed structures were not in agreement with published data. Consequently, revised structures for these compounds are proposed, whose correctness is unambiguously proven by total synthesis and comparison of the spectroscopic data. Key steps in all syntheses are Suzuki couplings for the construction of the central biaryl bond and Dakin reactions to supply further hydroxy groups required in these highly oxygenated substrates. Graphislactones A, C, and H, acylated graphislac- tone D and ulocladol were prepared in 8-11 steps with 7-20% yield starting with purchasable compounds, where the longest linear sequence consists of 5-9 steps. The syntheses are thus significantly shorter than the previously published syntheses of graphislactones A-D and of ulocladol. Graphis- lactones E and F were synthesized in 8 steps, where the longest linear sequences consist of 6 and 5 steps, respectively. They were isolated as the respective acetylated compounds with 25 and 10% yield.