Overexpressed or hyperactivated Rac1 as a target to treat hepatocellular carcinoma.

Despite novel targeted and immunotherapies, the prognosis remains bleak for patients with hepatocellular carcinoma (HCC), especially for advanced and/or metastatic forms. The rapid emergence of drug resistance is a major obstacle in the success of chemo-, targeted-, immuno-therapies of HCC. Novel targets are needed. The prominent roles of the small GTPase Rac1 in the development and progression of HCC are discussed here, together with its multiple protein partners, and the targeting of Rac1 with RNA-based regulators and small molecules. We discuss the oncogenic functions of Rac1 in HCC, including the contribution of Rac1 mutants and isoform Rac1b. Rac1 is a ubiquitous target, but the protein is frequently overexpressed and hyperactivated in HCC. It contributes to the aggressivity of the disease, with key roles in cancer cell proliferation, tumor metastasis and resistance to treatment. Small molecule targeting Rac1, indirectly or directly, have shown anticancer effects in HCC experimental models. Rac1-binding agents such as EHT 1864 and analogues offer novel opportunities to combat HCC. We discuss the different modalities to repress Rac1 overactivation in HCC with small molecules and the combination with reference drugs to promote cancer cell death and to repress cell invasion. We highlight the necessity to combine Rac1-targeted approach with appropriate biomarkers to select Rac1 activated tumors. Our analysis underlines the prominent oncogenic functions of Rac1 in HCC and discuss the modalities to target this small GTPase. Rac1 shall be considered as a valid target to limit the acquired and intrinsic resistance of HCC tumors and their metastatic potential.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder.

Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them-NSC23766 and EHT 1864-have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.

Rac1 as a therapeutic anticancer target: Promises and limitations.

Small molecule inhibitors of GTPases are increasingly considered for the treatment of multiple human pathologies. The GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1) plays major roles in vital cellular processes, notably in the control cell motility and dynamic, the regulation of oxidative stress, and in inflammatory and immune surveillance. As such, Rac1 is viewed as a potential target to combat cancers but also diverse inflammatory, metabolic, neurodegenerative, respiratory, cardiovascular, viral, and parasitic diseases. Potent and selective Rac1 inhibitors have been identified and designed, such as compounds GYS32661 and MBQ-167 both in preclinical development for the treatment of advanced solid tumors. The pleiotropic roles and ubiquitous expression of the protein can be viewed as limitations for anticancer approaches. However, the frequent overexpression and/or hyperactivation of the Rac1 in difficult-to-treat chemoresistant cancers, make Rac1 an attractive target in oncology. The key roles of Rac1 in multiple cellular pathways, together with its major implications in carcinogenesis, tumor proliferation and metastasis, support the development of small molecule inhibitors. The challenge is high and the difficulty shall not be underestimated, but the target is innovative and promising in combination with chemo- and/or immuno-therapy. Opportunities and challenges associated with the targeting of Rac1 are discussed.

Synthesis of a 35-member stereoisomer library of bistramide A: evaluation of effects on actin state, cell cycle and tumor cell growth.

Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.

Temporary silicon connection strategies in intramolecular allylation of aldehydes with allylsilanes.

Three gamma-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile to a series of beta-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane, with a range of Lewis and Brønsted acid activators provides an (E)-diene product. The mechanism of formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl ether connection react differently: thus in the presence of TMSOTf and a Brønsted acid scavenger, intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance in the reaction. This side product can be completely suppressed by using a sterically even more bulky diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed in these intramolecular allylations has been rationalized by using an electrostatic argument, which can also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction in the intramolecular allylation are more modest but can be significantly improved in some cases by using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-2,4-syn triols 28.

Using a temporary silicon connection in stereoselective allylation with allylsilanes: application to the synthesis of stereodefined 1,2,4-triols.

[reaction: see text]. Treatment of aldehyde 6 with TMSOTf, in the presence of a Brønsted acid scavenger, effects an intramolecular allylation to provide the oxasilacycle 7 as the major diastereoisomer. Tamao oxidation of the C-Si bond in 7 affords the corresponding 1,2,4-triol 9.

Stereoselective synthesis of allyl-C-mannosyl compounds: use of a temporary silicon connection in intramolecular allylation strategies with allylsilanes.

Methyl mannoside 16 containing an allyldimethylsilyl ether at C(2) was synthesized in nine steps from D-mannose. Reaction with TMSOTf in MeCN at room-temperature effected C-glycosylation to provide the alpha-allyl-C-mannosyl product 18 with excellent stereoselectivity. Crossover experiments over a range of reaction concentrations proved that reaction was proceeding via an intermolecular pathway rather than the hoped-for intramolecular delivery route. The exceptionally high stereoselectivity of this allylation in the presence of an acid-scavenger, 2,6-DTBMP, can be attributed to the allylsilyl ether 16 behaving as the allylating agent. Geometrical constraints in the seven-membered ring transition state account for the lack of intramolecular allyl transfer. Attaching a modified allylsilane 29a-c to C(2)OH of methyl mannoside 15 improved matters. Reaction of the tethered mannosides 27a-c with TMSOTf in the presence of 2,6-DTBMP in MeCN at rt provided a range of products, which depended on the size of the alkyl substituents at the silyl ether tether. Diene products were the major compounds irrespective of the size of the alkyl substituents at the silyl ether tether. Their formation can be understood by intramolecular allylation of the allylsilane on to the activated anomeric center, followed by collapse of the intermediate carbocation by preferential attack of an external nucleophile at the silyl ether tether, rather than at the allylic silicon center. A cascade of further reactions rationalizes the formation of the 2-dienyl-substituted tetrahydrofuran 30 and dienes 39 and 40. The desired beta-allyl-C-mannosyl products 42 and 43 were obtained, albeit in low yield, when bulky ethyl and isopropyl groups were employed at the silyl ether tether. Stereospecific oxidative cleavage of the silyl tether in 42 and 43 provided the corresponding stereodefined diols 44 and 45, respectively. Attempts to improve the yield and diastereoselectivity of the desired beta-allyl-C-mannosyls by moving to a sulfoxide mannosyl donor, which could be activated at low temperature, proved unsuccessful.