We previously investigated the utility of μ-oxo N,N′- bis(salicylidene)ethylenediamine iron (Fe(Salen)) nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen) nanoparticles should rapidly heat up in an alternating magnetic field (AMF), and we hypothesized that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy. Conventional hyperthermic particles are usually made of iron oxide, and thus cannot exhibit anti-cancer activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in cultured cancer cells, and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically guided delivery of the nanoparticles to the tumor, and AMF-induced heating of the nanoparticles to induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen) nanoparticles per se inhibited tumor growth before the other two modalities were applied. This inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue. When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor masses were dramatically reduced. These results indicate that our strategy of combined hyperthermia-chemotherapy using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a powerful new approach for cancer treatment.

The asymmetric epoxidation of allylic alcohols by metal catalysts, [1] though a widely used synthetic method, could gain even more practical applications if the following were realized: 1) employment of a ligand designed to achieve high enantioselectivity for Z olefins, 2) catalyst loading of less than 1 mol %, 3) reaction temperatures of 0 8C to room temperature over a shorter time, 4) use of aqueous tert-butyl hydroperoxide (TBHP) as an achiral oxidant instead of anhydrous TBHP, and 5) simple workup procedures for small epoxy alcohols. Many important improvements have been made to the methodology developed by Sharpless and co-workers for the titanium tartarate catalyzed asymmetric epoxidation. [2][3][4] Nonetheless, each of these approaches fails to fulfil the above criteria.[1-5] Herein, we report our recent progress on all five fronts.Recently, we developed a series of hydroxamic acid ligands and demonstrated that they were effective for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols. [6,7] These results suggested that several structural features of the hydroxamic acid significantly enhanced the rate and enantioselectivity of the reaction. However, the ligand deceleration effect was still observed in these cases. [6][7][8] To exclude this effect, we planned to design a new C 2 -symmetric bishydroxamic acid 1 that incorporated the following features: 1) an additional binding site with which 1 can chelate as a bidentate ligand to the metal center to complete the generation of a chiral vanadium/ligand complex more efficiently than the monohydroxamic acid and 2) an R group of the amide in 1 that is sufficiently large so the oxygen atom of the carbonyl group is directed towards the cyclohexane ring to minimize steric interaction and restrict its coordination with the metal center. Furthermore, the attachment of additional ligands to the vanadium center will also be restricted because of steric reasons. Thus, doubly or triply coordinated species, which are believed to be inactive, should not be generated from the bishydroxamic acid ligand, and consequently a ligand deceleration effect within the vanadium/1 catalytic system should not be problematic. [8] We devised a synthetic protocol for 1 from a readily available diamine tartrate salt (Scheme 1) so that the veracity of our hypothesis could be proved.[9] These reaction sequences can be carried out with satisfactory yields and without any purification to provide 4, from which we have prepared an array of diverse ligands 1 a-c.As expected, the use of a complex of vanadium with ligand 1 provided epoxy alcohols both in good yields with high enantioselectivities (Table 1).[9] The catalyst 5 a, derived from vanadium and 1 a, invariably induced excellent enantioselectivities during the epoxidation of trans-disubstituted and -trisubstituted allylic alcohols. The most gratifying aspect of this catalytic system was the excellent enantioselectivity observed during the epoxidation of cis-substituted allylic alcohols with catalyst 5 b, which was derived from...

Research on controlled drug delivery for cancer chemotherapy has focused mainly on ways to deliver existing anti-cancer drug compounds to specified targets, e.g., by conjugating them with magnetic particles or encapsulating them in micelles. Here, we show that an iron-salen, i.e., μ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)), but not other metal salen derivatives, intrinsically exhibits both magnetic character and anti-cancer activity. X-Ray crystallographic analysis and first principles calculations based on the measured structure support this. It promoted apoptosis of various cancer cell lines, likely, via production of reactive oxygen species. In mouse leg tumor and tail melanoma models, Fe(Salen) delivery with magnet caused a robust decrease in tumor size, and the accumulation of Fe(Salen) was visualized by magnetic resonance imaging. Fe(Salen) is an anti-cancer compound with magnetic property, which is suitable for drug delivery and imaging. We believe such magnetic anti-cancer drugs have the potential to greatly advance cancer chemotherapy for new theranostics and drug-delivery strategies.

Novel α-Amino Acid-Based Hydroxamic Acid Ligands for VanadiumCatalyzed Asymmetric Epoxidation of Allylic Alcohols.-A novel class of chiral ligands for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols, namely α-amino acid-based hydroxamic acid derivatives, is tested. Optimization regarding the amino acid side chain, the N-protecting group and the diarylmethyl group shows that best results are obtained for NTDH. A variety of mono-and disubstituted allylic alcohols are epoxidized with moderate to high yields and enantioselectivity, although long reaction times (up to one week) are necessary in the case of mono-substituted enols.

We previously reported that μ-oxo N,N’-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.