Reactivity Studies on the Lewis Base-Supported Terminal Uranium Imido Metallocene [η⁵‑1,3-(Me₃C)₂C₅H₃]₂UN(<i>p</i>‑tolyl)(dmap)

Addition of p-tolylNH2 to a toluene solution of [η5-1,3-(Me3C)2C5H3]2UMe2 (1) in the presence of 4-dimethylaminopyridine (dmap) yields the Lewis base-supported terminal uranium imido metallocene, [η5-1,3-(Me3C)2C5H3]2UN(p-tolyl)(dmap) (2), concomitant with methane release. Complex 2 undergoes a [2 + 2] cycloaddition with internal alkynes such as PhCCMe to form [η5-1,3-(Me3C)2C5H3]2U[N(p-tolyl)C(Me)C(Ph)] (3) exclusively. Formal [2 + 2] cycloadditions also initiate the reactions of complex 2 with ketones, thio-ketones, CS2, isothiocyanates, and seleno-ketones, but these [2 + 2] cycloaddion products are too unstable to be isolated, yielding dimeric oxido, sulfido, and selenido complexes, respectively. In the reaction with esters, carbodiimides, acyl nitriles, chlorosilanes, and bis(catecholato)diboron (B2cat2), uranium(IV) alkoxido amidate, guanidato, amidinato cyanido, amido chloride, and amido catecholate complexes are formed, respectively, indicating that this imido moiety may also act as a nucleophile. Moreover, the imido moiety in complex 2 may also engage in deprotonation reactions, as shown by its reactivity with the carboxamide PhCONH(p-tolyl), the organic nitriles PhCH2CN, Ph2CHCN, PhCN, and 1,4-(CH2)4(CN)2 to yield the uranium(IV) bis-amidate [η5-1,3-(Me3C)2C5H3]2U[OC(Ph)N(p-tolyl)]2 (8), the uranium(IV) iminato amido complexes [η5-1,3-(Me3C)2C5H3]2U[N(p-tolyl)C(CH2Ph)NH](NCCHPh) (11), [η5-1,3-(Me3C)2C5H3]2U[N(p-tolyl)C(CHPh2)NH](NCCPh2) (12), and [η5-1-{NC(Ph)NC(Ph)}-2,4-(Me3C)2C5H2][η5-1,3-(Me3C)2C5H3]U[N(p-tolyl)C(Ph)NH] (15), and the dimeric uranium(IV) imido {[η5-1,3-(Me3C)2C5H3]2UN(C5H6)CN}2 (13), respectively. Furthermore, 2 may also be doubly oxidized with organic azides (RN3), forming the uranium(VI) bis-imido metallocenes [η5-1,3-(Me3C)2C5H3]2UN(p-tolyl)(NR) (R = p-tolyl (19), mesityl (20)). Nevertheless, addition of Ph2S2 or Ph2Se2 to complex 2 results in ligand redistribution processes, yielding the uranium(VI) bis-imido complexes U[N(p-tolyl)]2(SPh)2(dmap)2 (21) and [η5-1,3-(Me3C)2C5H3]U[N(p-tolyl)]2(SePh)(dmap)2 (22) in low yield, respectively

Synthesis, Structures, and Reactivity of Single and Double Cyclometalated Complexes Formed by Reactions of [Cp*MCl₂]₂ (M = Ir and Rh) with Dinaphthyl Phosphines

Reactions of two dinaphthyl phosphines with [Cp*IrCl2]2 have been carried out. In the case of di­(α-naphthyl)­phenylphosphine (1a), a simple P-coordinated neutral adduct 2a is obtained. However, tert-butyldi­(α-naphthyl)­phenylphosphine (1b) is cyclometalated to form [Cp*IrCl­(P^C)] (3b). Complexes 2a and 3a undergo further cyclometalation to give the corresponding double cyclometalated complexes [Cp*Ir­(C^P^C)] (4a,b) upon heating. In the presence of sodium acetate, reactions of 1a,b with [Cp*IrCl2]2 directly afford the final double cyclometalated complexes (4a,b). In the absence of acetate, [Cp*RhCl2]2 shows no reaction with 1a,b, whereas with acetate the reactions form the corresponding single cyclometalated complexes [Cp*RhCl­(P^C)] (5a,b), which react with tBuOK to form the corresponding rhodium hydride complexes (6a,b). Treatment of 4a with CuCl2 or I2 leads to opening of two Ir–C σ bonds to yield the corresponding P-coordinated iridium dihalide (7 or 8) by means of an intramolecular C–C coupling reaction. A new chiral phosphine (11) is formed by the ligand-exchange reaction of 8 with PMe3. Reactions of the single cycloiridated complex 3b with terminal aromatic alkynes result in the corresponding five- and six-membered doubly cycloiridated complex 12 and/or η2-alkene coordinated complexes 13–15; the latter discloses that the electronic effect of terminal alkynes affects the regioselectivity. While the single cyclorhodated complex 5b reacts with terminal aromatic alkynes to form the corresponding six-membered cyclometalated complexes 16a–c by vinylidene rearrangement/1,1-insertion. Plausible pathways for formation of insertion products 13–16 were proposed. Molecular structures of twelve new complexes were determined by X-ray diffraction

Synthesis, Structures, and Reactivity of Single and Double Cyclometalated Complexes Formed by Reactions of [Cp*MCl₂]₂ (M = Ir and Rh) with Dinaphthyl Phosphines

Reactions of two dinaphthyl phosphines with [Cp*IrCl₂]₂ have been carried out. In the case of di­(α-naphthyl)­phenylphosphine (<b>1a</b>), a simple P-coordinated neutral adduct <b>2a</b> is obtained. However, <i>tert</i>-butyldi­(α-naphthyl)­phenylphosphine (<b>1b</b>) is cyclometalated to form [Cp*IrCl­(P^C)] (<b>3b</b>). Complexes <b>2a</b> and <b>3a</b> undergo further cyclometalation to give the corresponding double cyclometalated complexes [Cp*Ir­(C^P^C)] (<b>4a</b>,<b>b</b>) upon heating. In the presence of sodium acetate, reactions of <b>1a</b>,<b>b</b> with [Cp*IrCl₂]₂ directly afford the final double cyclometalated complexes (<b>4a</b>,<b>b</b>). In the absence of acetate, [Cp*RhCl₂]₂ shows no reaction with <b>1a</b>,<b>b</b>, whereas with acetate the reactions form the corresponding single cyclometalated complexes [Cp*RhCl­(P^C)] (<b>5a</b>,<b>b</b>), which react with ^<i>t</i>BuOK to form the corresponding rhodium hydride complexes (<b>6a</b>,<b>b</b>). Treatment of <b>4a</b> with CuCl₂ or I₂ leads to opening of two Ir–C σ bonds to yield the corresponding P-coordinated iridium dihalide (<b>7</b> or <b>8</b>) by means of an intramolecular C–C coupling reaction. A new chiral phosphine (<b>11</b>) is formed by the ligand-exchange reaction of <b>8</b> with PMe₃. Reactions of the single cycloiridated complex <b>3b</b> with terminal aromatic alkynes result in the corresponding five- and six-membered doubly cycloiridated complex <b>12</b> and/or η²-alkene coordinated complexes <b>13–15</b>; the latter discloses that the electronic effect of terminal alkynes affects the regioselectivity. While the single cyclorhodated complex <b>5b</b> reacts with terminal aromatic alkynes to form the corresponding six-membered cyclometalated complexes <b>16a–c</b> by vinylidene rearrangement/1,1-insertion. Plausible pathways for formation of insertion products <b>13–16</b> were proposed. Molecular structures of twelve new complexes were determined by X-ray diffraction

Self-Assembled Gemcitabine Prodrug Nanoparticles Show Enhanced Efficacy against Patient-Derived Pancreatic Ductal Adenocarcinoma

Effective new therapies for pancreatic ductal adenocarcinoma (PDAC) are desperately needed as the prognosis of PDAC patients is dismal and treatment remains a major challenge. Gemcitabine (GEM) is commonly used to treat PDAC; however, the clinical use of GEM has been greatly compromised by its low delivery efficacy and drug resistance. Here, we describe a very simple yet cost-effective approach that synergistically combines drug reconstitution, supramolecular nanoassembly, and tumor-specific targeting to address the multiple challenges posed by the delivery of the chemotherapeutic drug GEM. Using our developed PUFAylation technology, the GEM prodrug was able to spontaneously self-assemble into colloidal stable nanoparticles with sub-100 nm size on covalent attachment of hydrophobic linoleic acid via amide linkage. The prodrug nanoassemblies could be further refined by PEGylation and PDAC-specific peptide ligand for preclinical studies. In vitro cell-based assays showed that not only were GEM nanoparticles superior to free GEM but also the decoration with PDAC-homing peptide facilitated the intracellular uptake of nanoparticles and thereby augmented the cytotoxic activity. In two separate xenograft models of human PDAC, one of which was a patient-derived xenograft model, the administration of targeted nanoparticles resulted in marked inhibition of tumor progression as well as alleviated systemic toxicity. Together, these data unequivocally confirm that the hydrophilic and rapidly metabolized drug GEM can be feasibly transformed into a pharmacologically efficient nanomedicine through exploiting the PUFAylation technology. This strategy could also potentially be applied to rescue many other therapeutics that show unfavorable outcomes in the preclinical studies because of pharmacologic obstacles

Synthesis and Reactivity of the Uranium Bipyridyl Metallocene [η⁵‑1,3-(Me₃C)₂C₅H₃]₂U(bipy)

The addition of potassium graphite (KC8) to a mixture of [η5-1,3-(Me3C)2C5H3]2UCl2 (1) and 2,2′-bipyridine forms the uranium bipyridyl metallocene, [η5-1,3-(Me3C)2C5H3]2U(bipy) (2) in good yield, which is an excellent starting material for small molecule activation. Two major reactivity patterns have been identified for 2: (a) in the presence of a hydrazine derivative (PhNH)2, Ph2E2 (E = S and Se), AgF, alkynes, and a variety of heterounsaturated molecules, such as ketazine (Ph2CN)2, diazenes, pyridine N-oxide, organic azides, and CS2, it acts as the synthetic equivalent for the [η5-1,3-(Me3C)2C5H3]2U(II) fragment. (b) Upon addition of thio-ketone Ph2CS; aldehyde p-BrPhCHO; ketones Ph2CO, (CH2)5CO, and 1-indanone; amidate PhCONH (p-tolyl); lactide; seleno-ketone (p-MeOPh)2CSe; imine (p-tolyl)2CNH; ketazine (PhCHN)2; and nitriles Me3CCN, PhCN, and C6H11CN, C–C coupling occurs to furnish [η5-1,3-(Me3C)2C5H3]2U[(bipy)(Ph2CS)] (20), [η5-1,3-(Me3C)2C5H3]2U[(bipy)(p-BrPhCHO)] (21), [η5-1,3-(Me3C)2C5H3]2U[(bipy)(Ph2CO)] (22), [η5-1,3-(Me3C)2C5H3]2U[(bipy){(CH2)5CO}] (23), [η5-1,3-(Me3C)2C5H3]2U[(bipy)(1-C8H8CO)] (24), [η5-1,3-(Me3C)2C5H3]2U[(bipy){PhCONH(p-tolyl)}] (25), {[η5-1,3-(Me3C)2C5H3]2U(bipy)(C3H4O2)}2 (26), [η5-1,3-(Me3C)2C5H3]2U[(bipy){(p-MeOPh)2CSe}] (27), [η5-1,3-(Me3C)2C5H3]2U[(bipy){(p-tolyl)2CNH}] (28), [η5-1,3-(Me3C)2C5H3]2U[(bipy)(PhCHNNCHPh)] (29), [η5-1,3-(Me3C)2C5H3]2U[(bipy)(Me3CCN)] (31), [η5-1,3-(Me3C)2C5H3]2U[(C10H7N2)C(Ph)NH] (32), and [η5-1,3-(Me3C)2C5H3]2U[(C10H7N2)C(C6H11)NH] (33), respectively. However, from the reaction of 2 with thiazole, the dimeric sulfido complex {[η5-1,3-(Me3C)2C5H3]U[(C10H7N2)C(H)NCHCHS]}2 (30) is isolated, while the addition of CuI to complex 2 induces a single-electron transfer process to yield the uranium(III) iodide complex [η5-1,3-(Me3C)2C5H3]2U(I)(bipy) (18)

Influence of the 1,2,4-Tri-<i>tert</i>-butylcyclopentadienyl Ligand on the Reactivity of the Uranium Bipyridyl Metallocene [η⁵‑1,2,4-(Me₃C)₃C₅H₂]₂U(bipy)

The uranium bipyridyl metallocene, [η5-1,2,4-(Me3C)3C5H2]2U(bipy) (2), prepared from [η5-1,2,4-(Me3C)3C5H2]2UCl2 (1) and 2,2′-bipyridine in the presence of potassium graphite (KC8) has been evaluated in small-molecule activation. In contact with AgF, Ph2E2 (E = S, Se), (PhNH)2, (PhCHN)2, diazenes, pyridine N-oxide, organic azides, diazoalkanes, Ph2CS, and Ph2CO, it behaves as a synthon for the [η5-1,2,4-(Me3C)3C5H2]2U(II) fragment. In contrast, C–C bond coupling occurs when 2 is treated with (CH2)5CO, p-MePhCHO, and p-ClPhCHO to furnish [η5-1,2,4-(Me3C)3C5H2]2U[(bipy){(CH2)5CO}] (19), [η5-1,2,4-(Me3C)3C5H2]2U[(bipy)(p-MePhCHO)] (20), and [η5-1,2,4-(Me3C)3C5H2]2U[(bipy)(p-ClPhCHO)] (21), respectively. Moreover, a single-electron transfer (SET) process ensues after the addition of CuI to 2 to yield the uranium(III) iodide complex [η5-1,2,4-(Me3C)3C5H2]2UI (3). A comparison with the other uranium bipyridyl metallocene derivatives shows that minor variations in the coordinated cyclopentadienyl ligands changes the reactivity of these compounds

Comparative Transcriptome Analysis in the Hepatopancreas Tissue of Pacific White Shrimp <i>Litopenaeus vannamei</i> Fed Different Lipid Sources at Low Salinity

<div><p>RNA-seq was used to compare the transcriptomic response of hepatopancreas in juvenile <i>Litopenaeus vannamei</i> fed three diets with different lipid sources, including beef tallow (BT), fish oil (FO), and an equal combination of soybean oil + BT + linseed oil (SBL) for 8 weeks at 3 practical salinity unit (psu). A total of 9622 isogenes were annotated in 316 KEGG pathways and 39, 42 and 32 pathways significantly changed in the paired comparisons of FO vs SBL, BT vs SBL, or FO vs BT, respectively. The pathways of glycerolipid metabolism, linoleic acid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, fatty acid biosynthesis, fatty acid elongation, fatty acid degradation, and biosynthesis of unsaturated fatty acid were significantly changed in all paired comparisons between dietary lipid sources, and the pathways of glycerolipid metabolism, linoleic acid metabolism, arachidonic acid metabolism and glycerophospholipid metabolism significantly changed in the FO vs SBL and BT vs SBL comparisons. These pathways are associated with energy metabolism and cell membrane structure. The results indicate that lipids sources affect the adaptation of <i>L</i>. <i>vannamei</i> to low salinity by providing extra energy or specific fatty acids to change gill membrane structure and control iron balance. The results of this study lay a foundation for further understanding lipid or fatty acid metabolism in <i>L</i>. <i>vannamei</i> at low salinity.</p></div

Pathway of fatty acid elongation.

<p>Pathway of fatty acid elongation.</p

Pathway of glycerolipid metabolism.

<p>Pathway of glycerolipid metabolism.</p

Small-Molecule Activation Mediated by [η⁵‑1,3-(Me₃Si)₂C₅H₃]₂U(bipy)

The uranium bipyridyl metallocene, [η5-1,3-(Me3Si)2C5H3]2U­(bipy) (2), is readily accessible in good yield by adding potassium graphite (KC8) to a mixture of [η5-1,3-(Me3Si)2C5H3]2UCl2 (1) and 2,2′-bipyridine. Compound 2 was fully characterized and employed for small-molecule activation. It has been demonstrated that 2 may serve as a synthon for [η5-1,3-(Me3Si)2C5H3]2U­(II) fragment in the presence of Ph2E2 (E = S, Se), alkynes, and a variety of hetero-unsaturated molecules such as diazabutadienes, azine (Ph2CN)2, o-benzoquinone, pyridine N-oxide, CS2, isothiocyanates, and organic azides. However, upon exposure of 2 to thio-ketone Ph2CS, aldehyde p-MePhCHO, ketone Ph2CO, imine PhCHNPh, azine (PhCHN)2, and nitrile PhCN, it may also promote C–C coupling reactions forming [η5-1,3-(Me3Si)2C5H3]2U­[(bipy)­(Ph2CS)] (16), [η5-1,3-(Me3Si)2C5H3]2U­[(bipy)­(p-MePhCHO)] (17), [η5-1,3-(Me3Si)2C5H3]2U­[(bipy)­(Ph2CO)] (18), [η5-1,3-(Me3Si)2C5H3]2U­[(bipy)­(PhCHNPh)] (19), [η5-1,3-(Me3Si)2C5H3]2U­[(bipy)­(PhCHNNCHPh)] (20), and [η5-1,3-(Me3Si)2C5H3]2U­[(N2C10H7C­(Ph)­NH)] (22), respectively, in quantitative conversion. Furthermore, in the presence of CuI, a single-electron transfer (SET) process is observed to yield the uranium­(III) iodide complex [η5-1,3-(Me3Si)2C5H3]2U­(I)­(bipy) (15)