Clickable bisreactive small gold nanoclusters for preparing multifunctionalized nanomaterials: application to photouncaging of an anticancer molecule.

In this study, we successfully synthesized a small-sized gold nanocluster (2 nm) coated with homogeneous tripeptides bearing azido and amino groups that enable facile multifunctionalizations. Using sodium phenoxide to reduce tetrachloroauric(iii) acid in the presence of the cysteine-containing tripeptide, we efficiently prepared the gold nanoclusters without damaging the azido group. We then utilized this clickable bisreactive nanocluster as a versatile platform for synthesizing multifunctionalized gold nanomaterials.

C-Cyanation of Aryl Fluorides via Nickel and Lithium Chloride-Mediated C-F Bond Activation.

Aryl fluorides are expected to be useful as radiolabeling precursors due to their chemical stability and ready availability. However, direct radiolabeling via carbon-fluorine (C-F) bond cleavage is a challenging issue due to its significant inertness. Herein, we report a two-phase radiosynthetic method for the ipso- C-cyanation of aryl fluorides to obtain [ C]aryl nitriles via nickel-mediated C-F bond activation.

Palladium(ii)-mediated rapid C-cyanation of (hetero)arylborons.

A palladium(ii)-mediated rapid C-cyanation of (hetero)arylborons with [C]NHCN/NH has been developed using bench-stable and readily available reagents. The method showed excellent functional-group tolerance, and allowed the highly efficient synthesis of a wide range of [C]cyanoarenes, including PET tracers for aromatase imaging. A mechanistic study of the C-cyanation suggests the instantaneous formation of a mono[C]cyanopalladium(ii) complex that reacts smoothly with arylborons.

A novel (11)C-labeled thymidine analog, [(11)C]AZT, for tumor imaging by positron emission tomography.

Background: Nucleoside analogs labeled with positrons, such as (11)C and (18)F, are considered valuable in visualizing the proliferative activity of tumor cells in vivo using positron emission tomography (PET). We recently developed the (11)C-labeled thymidine analogs [(11)C]zidovudine ([(11)C]AZT) and [(11)C]stavudine ([(11)C]d4T) via the Pd(0)-Cu(I) co-mediated rapid C-C coupling reaction. In this study, to examine whether [(11)C]AZT and [(11)C]d4T might be useful for visualization of tumors in vivo, we performed PET imaging, tissue distribution studies, and metabolite analysis in tumor-bearing mice.

Efficient syntheses of [¹¹C]zidovudine and its analogs by convenient one-pot palladium(0)-copper(I) co-mediated rapid C-[¹¹C]methylation.

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.

Pd0-mediated rapid cross-coupling reactions, the rapid C-[11C]methylations, revolutionarily advancing the syntheses of short-lived PET molecular probes.

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short-lived positron-emitting radionuclide. New methodologies for introducing representative short-lived radionuclides, (11)C and (18)F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C-[(11)C]methylations and C-[(18)F]fluoromethylations using rapid Pd(0)-mediated cross-coupling reactions between [(11)C]methyl iodide (sp(3)-hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp(2) (phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp(3) (benzyl and cinnamyl)-hybridized carbons; and [(18)F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short-lived (11)C- or (18)F-labeled PET molecular probes to promote in vivo molecular imaging studies.

Highly efficient syntheses of [methyl-11C]thymidine and its analogue 4'-[methyl-11C]thiothymidine as nucleoside PET probes for cancer cell proliferation by Pd(0)-mediated rapid C-[11C]methylation.

Pd(0)-mediated rapid couplings of CH(3)I (and then [(11)C]CH(3)I) with excess 5-tributylstannyl-2'-deoxyuridine and -4'-thio-2'-deoxyuridine were investigated for the syntheses of [methyl-(11)C]thymidine and its stable analogue, 4'-[methyl-(11)C]thiothymidine as PET probes for cancer diagnosis. The previously reported conditions were attempted using Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3) (1 : 4 in molar ratio) at 130 °C for 5 min in DMF, giving desired products only in 32 and 30% yields. Therefore, we adapted the current reaction conditions developed in our laboratory for heteroaromatic compounds.

Development of novel oxygen-independent photosensitizers.

We proposed a strategy of photooxidizer-reduction activated alkylator (P-A) hybrid molecule to develop novel oxygen-independent photosensitizers. Two prototypes of such photosensitizers camptothecin-indolequinone (CPT-IQ) and camptothecin-nitrofuryl (CPT-NF) was designed and prepared. A mechanism of photo-induced oxidation and alkylation of 2'-deoxyguanosine by CPT-IQ was investigated.

Current molecular design of intelligent drugs and imaging probes targeting tumor-specific microenvironments.

To address the specific challenges of cancer therapy and diagnosis, a number of approaches have been advocated for the development of tumor-targeting antitumor drugs/prodrugs and non-invasive tumor molecular imaging probes. These intelligent drugs and probes are constructed from multi-functional molecular systems. This review focuses on the molecular design of drugs and imaging probes that target tumor-specific microenvironments such as angiogenesis and hypoxia.

Bioreduction activated prodrugs of camptothecin: molecular design, synthesis, activation mechanism and hypoxia selective cytotoxicity.

Several water-soluble derivatives (CPT3, CPT3a-d) of camptothecin (CPT) were synthesized, among which CPT3 bearing an N,N'-dimethyl-1-aminoethylcarbamate side-chain was further conjugated with reductively eliminating structural units of indolequinone, 4-nitrobenzyl alcohol and 4-nitrofuryl alcohol to produce novel prodrugs of camptothecin (CPT4-6). All CPT derivatives were of lower cytotoxicity than their parent compound of CPT. In contrast, CPT4 and CPT6 showed higher hypoxia selectivity of cytotoxicity towards tumor cells than CPT.

Aminopeptidase N/CD13 targeting fluorescent probes: synthesis and application to tumor cell imaging.

A family of fluorescein-peptide conjugates (CNP1-3) for aminopeptidase N (APN/CD13) targeting fluorescent probes were designed and synthesized. Among the three conjugates, CNP1 bearing tumor-homing cyclic peptide CNGRC, could selectively label APN/CD13 over-expressing on the surface of tumor cells of HT-1080, as identified by means of fluorescent microscopic cell imaging. CNP1 was shown to be a promising fluorescent probe applicable to tumor-targeting molecular imaging.

A new class of 5-fluoro-2'-deoxyuridine prodrugs conjugated with a tumor-homing cyclic peptide CNGRC by ester linkers: synthesis, reactivity, and tumor-cell-selective cytotoxicity.

Purpose: Tumor-targeting prodrugs of 5-fluoro-2'-deoxyuridine (5-FdUrd), which are chemical conjugations of 5-FdUrd with a tumor-homing cyclic peptide CNGRC by succinate and glutarate linkers, were synthesized to investigate the structural effects of linkers on the hydrolytic release of 5-FdUrd and the tumor-cell-selective cytotoxicity.

Methods: A solid phase synthesis method was used to produce 5-FdUrd prodrugs. The kinetics and efficiency of hydrolytic 5-FdUrd release from the prodrugs were investigated in phosphate buffer (PB), fetal bovine serum (FBS), HT-1080 cell lysate, MDA-MB-231 cell lysate, and MEM containing 10% FBS.

Synthesis and photochemical properties of photoactivated antitumor prodrugs releasing 5-fluorouracil.

A new family of antitumor prodrugs (1-3) of 5-fluorouracil (5-FU) possessing photolabile 2-nitrobenzyl chromophores have been designed and synthesized to investigate the efficiency and mechanism of photoactivated 5-FU release upon UV-irradiation at lambda(ex)= 365 nm. The photoactivated prodrug 3 derived from conjugation of 2 with a tumor-homing cyclic peptide Cys-Asn-Gly-Arg-Cys (CNGRC) was so designed as to manifest a tumor-targeting function.