Tun Cheng Chien

Practical synthesis of N -substituted cyanamides via tiemann rearrangement of amidoximes

A facile and general synthesis of various N-substituted cyanamides was accomplished by the Tiemann rearrangement of amidoximes with benzenesulfonyl chlorides (TsCl or o-NsCl) and DIPEA.

Analysis of UDP-D-apiose/UDP-D-xylose synthase-catalyzed conversion of UDP-D-apiose phosphonate to UDP-D-xylose phosphonate: Implications for a retroaldol-aldol mechanism

UDP-D-apiose/UDP-D-xylose synthase (AXS) catalyzes the conversion of UDP-D-glucuronic acid to UDP-D-apiose and UDP-D-xylose. An acetyl-protected phosphonate analogue of UDP-D-apiose was synthesized and used in an in situ HPLC assay to demonstrate for the first time the ability of AXS to interconvert the two reaction products. Density functional theory calculations provided insight into the energetics of this process and the apparent inability of AXS to catalyze the conversion of UDP-D-xylose to UDP-D-apiose. The data suggest that this observation is unlikely to be due to an unfavorable equilibrium but rather results from substrate inhibition by the most stable chair conformation of UDP-D-xylose. The detection of xylose cyclic phosphonate as the turnover product reveals significant new details about the AXS-catalyzed reaction and supports the proposed retroaldol-aldol mechanism of catalysis.

Mononuclear heterocyclic rearrangement: Synthesis of [5:5] bicyclic [c]-fused 3-aminopyrazoles via the N-N bond formation strategy

The formation of [5:5] bicyclic heterocyclic ring systems containing [c]pyrazoles, i.e. imidazo[4,5-c]pyrazole, pyrazolo[3,4-c]pyrazole, pyrrolo-[2,3-c]pyrazole, and pyrazolo[3,4-d][1,2,3]triazole, was accomplished by mononuclear heterocyclic rearrangement (MHR). The core pyrazole ring was formed based on a N-N bond formation strategy. The ring transformation of 5-substituted 3-(2-aminoaryl)-1,2,4-oxadiazoles (14, 15a-b, 16b and 33) under thermal conditions to the corresponding [5:5] bicyclic [c]-fused 3-aminopyrazole ring systems (17a, 18a-b, 20 and 34 respectively) was promoted by sodium hydride in DMF or DMSO. The ring transformation by MHR has provided a practical and general synthetic method for the derivatives of 3-aminoimidazo-[4,5-c]pyrazole (4), 3-aminopyrazolo[3,4-c]pyrazole (5), 3-aminopyrrolo[2,3-c]-pyrazole (6) and 6-aminopyrazolo[3,4-d][1,2,3]triazole (7).

Nucleosides. IX. Synthesis of Purine N 3,5′‐Cyclonucleosides and N 3,5′‐Cyclo‐2′,3′‐seconucleosides via Mitsunobu Reaction as TIBO‐like Derivatives

The Mitsunobu reaction was applied to prepare, in one step, purine N 3,5′‐cyclonucleosides 10a–d. A subsequent ring opening in the ribose moiety of the resultant N 3,5′‐nucleosides by sodium periodate led to the corresponding N 3,5′‐cyclo‐2′,3′‐seconucleosides. These products consist of 5‐, 6‐, and 7‐membered tricyclic system which is the basic skeleton of TIBO derivatives, known antiviral agents. #Previous paper in this series: Ref. 1. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

Abstract Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2α and hTop2β revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2β, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

CuI-Catalyzed intramolecular aminocyanation of terminal alkynes in N-(2-ethynylphenyl)-N-sulfonylcyanamides via Cu–vinylidene intermediates

CuI-Catalyzed intramolecular aminocyanation of terminal alkynes in N-(2-ethynylphenyl)-N-sulfonylcyanamides was initiated by the formation of Cu-acetylide to trigger N-CN bond cleavage of the N-sulfonylcyanamide moiety followed by CN migration to form a β-cyano Cu-vinylidene intermediate. Subsequently, the indole ring closure furnished the corresponding 1-sulfonyl-3-cyanoindoles.

Biomimetic Approach toward the Total Synthesis of rac-2-(Acylmethylene)pyrrolidine Alkaloids.

2-(Acylmethylene)pyrrolidine derivatives were synthesized via intermolecular decarbonylative Mannich reaction from various methyl ketones and 1-alkyl-1-pyrroliniums, generated in situ from 1-alkylprolines. This approach mimics the biosynthetic pathway and provides a direct access to a series of 2-(acylmethylene)pyrrolidine alkaloids, including hygrine, N-methylruspolinone, dehydrodarlinine, and ruspolinone.

Copper(i) iodide-catalyzed synthesis of N,N′-disubstituted guanidines from n-substituted cyanamides

A facile and effective synthesis of N-alkyl-N′-arylguanidines was accomplished by the reaction of N-arylcyanamides with various primary and secondary alkylamines, under the catalysis of copper(i) iodide and Xantphos in DMF. This methodology provides a direct access to versatile N,N′-disubstituted guanidine derivatives from N-arylcyanamides that can be readily prepared from the corresponding nitriles via Tiemann rearrangement.

Synthesis and Unexpected Oxidization of the Tricyclic Core of Ugibohlin, Isophakellin, and Styloguanidine

A series of 4-substituted 5,6,7,9-tetrahydropyrrolo[2,3-f]indolizin-9-ones, representing the tricyclic core skeleton of ugibohlin, isophakellin, and styloguanidine, were synthesized via an intramolecular Vilsmeier-Haack reaction. This reaction allows the chemoselective C-C bond formation between the pyrrole C3 and proline C5 of N-[(pyrrol-2-yl)carbonyl]prolinamides to construct the B-ring without the protection of the pyrrole nitrogen. Unexpected oxidizative property of the tricyclic core skeleton was observed, which could illuminate understanding of the biological formation of these marine secondary metabolites.

Green fluorescent protein chromophore derivative suppresses ultraviolet A-induced JNK-signalling and apoptosis in keratinocytes and adverse effects in zebrafish embryos

Solar ultraviolet (UV) light has been recognized as the important environmental hazard and contributes to diverse skin damage such as cell death, photoageing and even carcinogenesis. Revelation of harmful responses attributed to UVA radiation has promoted the development of photoprotective agents against UVA‐induced skin damage. In the present study, we tried to evaluate the potential protective effects of a synthetic green fluorescent protein (GFP) chromophore derivative, 4‐chlorobenzyldene‐1, 2‐dimethylimidazolinone (Cl‐BDI, called TC‐22) on UVA‐ and UVB‐ induced stress responses in skin. The HaCaT keratinocytes were used to evaluate the cellular effects. Zebrafish (Danio rerio), which is regarded as a useful and cost‐effective alternative to some mammalian models, was applied as the in vivo animal model. In HaCaT keratinocytes, TC‐22 was able to obviously decrease UVA‐induced cell death. Dissection of the UVA‐induced signalling pathways revealed that TC‐22 could suppress the activation of JNK and caspase 3, but not of ERK and p38. Reduction of UVA‐induced cleavage of caspase 3 and sub‐G1 phase accumulation by pretreatment of TC‐22 was also observed. In zebrafish, we showed that UVA irradiation could decrease the survival and hatching rate, suppress heart beats of embryos and enhance the pigmentation of larvae. Pretreatment of TC‐22 could significantly reverse UVA‐induced the suppression in hatching of eggs and heart beating of embryos and also lowered the UVA‐induced pigmentation in zebrafish. Collectively, we demonstrate that TC‐22, a GFP chromophore derivative, can ameliorate the UVA‐induced stress responses in both epidermal keratinocytes and zebrafish, suggesting the potential use of TC‐22 in photoprotection in the future.