ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Carcinoma, Pancreatic Ductal/metabolism , Cell Cycle Proteins/genetics , DNA Replication , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Pancreatic Neoplasms/metabolism , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Humans , Mice , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Protein Biosynthesis , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
Griseofulvin, an antifungal drug, has been shown in recent years to have anti-proliferative activities. We report here the synthesis of new analogs of griseofulvin, substituted in 2' by a sulfonyl group or in 3' by a sulfinyl or sulfonyl group. These compounds exhibit good anti-proliferative activities against SCC114 cells, an oral squamous carcinoma cell line showing pronounced centrosome amplification, and unexpected cytotoxic activities on HCC1937 cells, a triple negative breast cancer cell line resistant to microtubule inhibitors.
Subject(s)
Griseofulvin/chemical synthesis , Griseofulvin/pharmacology , Neoplasms/pathology , Sulfones/chemistry , Sulfoxides/chemistry , Cell Line, Tumor , Drug Resistance, Neoplasm , Griseofulvin/chemistry , HumansABSTRACT
(-)-Cryptopleurine 1 is one of the most potent anti-proliferative member of the phenanthroquinolizidine class of alkaloids. We report here the synthesis of (-)-6-O-desmethylcryptopleurine (-)-2 and (-)-6-O-desmethyl-(15R)-hydroxycryptopleurine (-)-4 in their enantiomerically enriched form through a convergent synthetic route, where the chirality is introduced by the use of commercially available (R)-methyl piperidine-2-carboxylate hydrochloride 17. Anti-proliferative activities of these compounds were evaluated on a panel of four cancer cell lines, revealing that compounds (-)-2 and (-)-4 are potent cytotoxic compared to cryptopleurine.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/physiology , Drug Evaluation, Preclinical/methods , HumansABSTRACT
Analogues of the sponge meroterpenoid liphagal have been synthesized and evaluated for inhibition of PI3Kα and PI3Kγ as part of a program aimed at developing new isoform-selective PI3K inhibitors. One of the analogues, compound 24, with IC50 values of 66 nM against PI3Kα and 1840 nM against PI3Kγ, representing a 27-fold preference for PI3Kα, exhibited enhanced chemical stability and modestly enhanced potency and selectivity compared with the natural product liphagal.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Porifera , Terpenes/chemical synthesis , Animals , Drug Stability , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Phosphatidylinositol 3-Kinase/chemistry , Stereoisomerism , Structure-Activity Relationship , Terpenes/chemistryABSTRACT
[structure: see text] Liphagal (1), a selective inhibitor of PI3K alpha, has been isolated from the marine sponge Aka coralliphaga collected in Dominica. The "liphagane" meroterpenoid carbon skeleton of liphagal (1) is new. A biomimetic total synthesis has been used to confirm the constitution of liphagal (1) and support a proposed biogenesis.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Porifera/chemistry , Terpenes/chemical synthesis , Androstadienes/pharmacology , Animals , Chromones/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Morpholines/pharmacology , Terpenes/isolation & purification , Terpenes/pharmacology , Tumor Cells, Cultured , WortmanninABSTRACT
[reaction: see text] Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides cyclobutanones.
ABSTRACT
A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into heterogeneous polycyclic compounds in good yields. This leads interestingly to the formation of isoindols, isoindolinones, and pyridoisoindolones. [reaction: see text]
