David S. Grierson

Ligandless Microwave-Assisted Pd/Cu-Catalyzed Direct Arylation of Oxazoles

An efficient microwave-assisted palladium/copper co-mediated direct arylation of oxazoles with aryl bromides under ligandless conditions has been developed. The method is functional group tolerant and provides rapid access to medicinally relevant compounds in good yields. Coupled to the van Leusen oxazole ring synthesis, this methodology is illustrated by an expedient two-step synthesis of the four 2,5-diaryloxazole alkaloids texamine, texaline, balsoxin, and O-Me-halfordinol from commercially available starting materials.

Stereoselective direct copper-catalyzed alkenylation of oxazoles with bromoalkenes.

A copper-catalyzed direct alkenylation of oxazoles with bromoalkenes has been developed. The method is both regio- and stereoselective and tolerates a variety of functional groups. A wide range of 2-E-vinyl-substituted oxazoles were obtained in high yields including the highly fluorescent alkaloid annuloline.

Synthesis, Cellular Internalization and Photodynamic Activity of Glucoconjugated Derivatives of Tri and Tetra(meta-hydroxyphenyl)chlorins

Glucoconjugated tri and tetra(meta-hydroxyphenyl)chlorins have been synthesized in order to explore how glucoconjugation of the macrocycle affects the photoactivity of the molecule. Internalization processes, photosensitizing efficacy of TPC(m-O-GluOH)(3) and TPC(m-O-GluOH)(4), in HT29 human adenocarcinoma cells have been compared to those of tetra(meta-hydroxyphenyl) chlorin (m-THPC, Foscan). The tetra glucoconjugated chlorin, TPC(m-O-GluOH)(4), was found to be poorly internalized and weakly photoactive. In contrast, the asymmetric and more amphiphilic compound TPC(m-O-GluOH)(3), exhibited superior phototoxicity compared to m-THPC. Drug concentration, temperature and sodium azide effects indicated that TPC(m-O-GluOH)(3) internalization partly proceeds via an active receptor-mediated endocytosis mechanism. Cellular uptake appeared as a saturable process and remained 30% lower than for mTHPC. However, a maximum phototoxicity in HT29 cells (survival fraction of 2+/-0.6%) were observed for concentration as low as 2 microM. A 4-fold higher concentration of m-THPC was necessary to observe the same level of photoactivity. This higher phototoxicity has been correlated to a greater mitochondrial affinity. On the basis of these results, work is in progress to further evaluate the potential of glycosylated chlorins in photodynamic therapy (PDT).

Small-Molecule Inhibition of HIV pre-mRNA Splicing as a Novel Antiretroviral Therapy to Overcome Drug Resistance

The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16) that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell–tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.

New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights

Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence of implication in growth dysregulation and apoptosis resistance, making it a relevant target for cancer therapy. Several CK2 inhibitors have been developed showing variable efficiency, emphasizing the need to expand the chemical diversity of those inhibitors. We report the identification and characterization of 2,8‐difurandicarboxylic acid derivatives as a new class of nanomolar ATP‐competitive inhibitors. Selectivity profiling pointed out proviral insertion Moloney virus kinases (Pim kinases) as the only other kinases that are significantly inhibited. By combining structure‐activity relationship analysis with structural determination, we were able to determine the binding mode of these inhibitors for both kinases and to explain their strong inhibitory potency. Essential chemical features necessary for activity on both kinases were then identified. The described compounds are not cell permeable: however, they could provide a lead for developing novel inhibitors usable also in vivo. Given the similar but not redundant pathophysiological functions of CK2 and Pim family members, such inhibitors would provide new attractive leads for targeted cancer therapy. This work highlights that 2 functionally related kinases from different kinome branches display exquisite sensitivity to a common inhibitor.—López‐Ramos, M., Prudent, R., Moucadel, V., Sautel, C. F., Barette, C., Lafanechère, L., Mouawad, L., Grierson, D., Schmidt, F., Florent, J.‐C., Filippakopoulos, P., Bullock, A. N., Knapp, S., Reiser, J.‐B., Cochet, C. New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights. FASEB J. 24, 3171–3185 (2010). www.fasebj.org

2-cyano Δ3 piperidines vi1 : a general method for the stereoselective synthesis of cis and trans 2,6-dialkylpiperidine alkaloids

The cis 2,6-dialkylpiperidine alkaloid (±) dihydro-pinidine 7b and the trans alkaloid (±) solenopsin A 5a were synthesized from a common α-aminonitrile synthon 1. The key step in this synthesis was the stereoselective reductive decyanation of the 1-benzyl-2cyano-2′, 6-dialkylpiperidines 3a and 3b.

Asymmetric synthesis VIII: Biogenetically patterned approach to the chiral total synthesis of (−)-pumiliotoxin-C☆

(−)-Pumiliotoxin-C and the (+)-9,10-trans isomer 10 were prepared in six steps from the chiral (+)-2-cyano-6-oxazolopiperidine synthon 3.

Pharmacological inhibition of LIM Kinase stabilizes microtubules and inhibits neoplastic growth

The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubule-stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubule-targeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment.

Benzoindoloquinolines interact with DNA tetraplexes and inhibit telomerase

Telomeric G-rich single-stranded DNA can adopt a G-tetraplex structure which has been shown to inhibit telomerase activity. We have examined benzoindoloquinolines derivatives for their ability to stabilize an intramolecular G-quadruplex. The increase in T(m) value of the G-quadruplex was associated with telomerase inhibition in vitro.

Asymmetric synthesis XV : enantiospecific synthesis of (+) and (−) isonitramines from a common chiral intermediate

Abstract The enantiospecific synthesis of (+) and (−) isonitramines 7 has been achieved from a common chiral intermediate 5 ; this key compound was formed by condensation of two molar equivalents of glutaraldehyde with one mole of (−) phenylglycinol.