ABSTRACT
We take advantage of the Pummerer oxidative annulation reaction to extend PAHs through the formation of an intramolecular C-O bond with a suitable phenol substituent. Depending on the peripheral topology of the PAH precursor (e.g., pyrene, boron-dipyrromethene, or perylene diimide) five-, six-, and seven-membered O-containing rings could be obtained. The effect of the O-annulations on the optoelectronic properties were studied by various methods with the pyrano-annulated pyrene and BODIPY derivatives depicting quantitative emission quantum yields.
ABSTRACT
Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , BRCA2 Protein/metabolism , Pancreatic Neoplasms/drug therapy , Phthalazines/pharmacology , Piperazines/pharmacology , Rad51 Recombinase/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Antineoplastic Agents/chemistry , BRCA2 Protein/genetics , Cell Line, Tumor , DNA Damage/drug effects , Drug Discovery , Drug Synergism , Homologous Recombination/drug effects , Humans , Models, Molecular , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Phthalazines/chemistry , Piperazines/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Protein Interaction Maps/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Synthetic Lethal Mutations/drug effectsABSTRACT
Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
Subject(s)
Antineoplastic Agents/chemistry , BRCA2 Protein/metabolism , Homologous Recombination/drug effects , Pancreatic Neoplasms/drug therapy , Rad51 Recombinase/metabolism , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , BRCA2 Protein/genetics , Cell Line, Tumor , Drug Synergism , Humans , Molecular Mimicry , Mutation , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phthalazines/therapeutic use , Piperazines/therapeutic use , Protein Binding/drug effects , Protein Binding/genetics , Triazoles/chemical synthesisABSTRACT
Novel amphiphilic guanine derivatives, here named Gua1 and Gua2, have been prepared through few, simple and efficient synthetic steps. In ion transport experiments through phospholipid bilayers, carried out to evaluate their ability to mediate H(+) transport, Gua2 showed high activity. When this compound was investigated for ion-selective transport activities, no major differences were observed in the behaviour with cations while, in the case of anions, selective activity was observed in the series I(-)>Br(-)>Cl(-)>F(-). The bioactivity of these guanine analogues has been evaluated on a panel of human tumour and non-tumour cell lines in preliminary in vitro cytotoxicity assays, showing a relevant antiproliferative profile for Gua2.
Subject(s)
Guanine/chemistry , Ion Transport , Cell Line , Cell Line, Tumor , Drug Screening Assays, Antitumor , Guanine/chemical synthesis , Guanine/pharmacology , HumansABSTRACT
The [Pd(dppp)(OTf)2] complex acts as an efficient transporter of halide anions, in particular the biologically relevant chloride anion, across a phospholipid bilayer.
Subject(s)
Coordination Complexes/chemistry , Palladium/chemistry , Phosphatidylcholines/chemistry , Phosphatidylglycerols/chemistry , Anions , Ion Transport , Liposomes , Mesylates/chemistry , Phosphines/chemistry , PhospholipidsABSTRACT
A small library of sugar-modified guanosine derivatives has been prepared, starting from a common intermediate, fully protected on the nucleobase. Insertion of myristoyl chains and of diverse hydrophilic groups, such as an oligoethylene glycol, an amino acid or a disaccharide chain, connected through in vivo reversible ester linkages, or of a charged functional group provided different examples of amphiphilic guanosine analogues, named G1-G7 herein. All of the sugar-modified derivatives were positive in the potassium picrate test, showing an ability to form G-tetrads. CD spectra demonstrated that, as dilute solutions in CHCl(3), distinctive G-quadruplex systems may be formed, with spatial organisations dependent upon the structural modifications. Two compounds, G1 and G2, proved to be good low-molecular-weight organogelators in polar organic solvents, such as methanol, ethanol and acetonitrile. Ion transportation experiments through phospholipid bilayers were carried out to evaluate their ability to mediate H(+) transportation, with G5 showing the highest activity within the investigated series. Moreover, G3 and G5 exhibited a significant cytotoxic profile against human MCF-7 cancer cells in in vitro bioassays.
