Directed synthesis of all four pure stereoisomers of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A

The first preparation of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A and its likewise naturally occurring minor atropisomer, in an atropisomerically pure form, is described. The synthesis succeeded by resolution of the already rotationally hindered, and thus atropo-diastereomeric acetamide precursors, which were then, without major loss of stereochemical information, cyclized to the respective target molecules. The strategy was applied to the first synthesis of the regioisomeric product ancistrocladinium D, likewise in a stereochemically pure form

First atroposelective total synthesis of enantiomerically pure ancistrocladidine and ancistrotectorine

The first regio‐ and stereoselective total synthesis of the axially chiral 7,3′‐coupled naphthylisoquinoline alkaloids ancistrocladidine (1) and ancistrotectorine (2) has been described. Both possess a 7,3′‐coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis‐array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the “lactone method”: the two molecular halves, which were activated in an “inverse‐halogenated” form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold

Effects of the novel polyphenol conjugate DPP-23 on head and neck squamous cell carcinoma cells in vitro

Despite partial advances in therapy for patients suffering from head and neck squamous cell carcinomas (HNSCC), prognosis still remains poor with minimal improvement in survival for over the last several decades. Some agents found are known to cause cancer cell death in vitro by promoting cellular reactive oxygen species (ROS) accumulation. This is particularly of interest as some cancer cells are more sensitive to ROS than normal cells. It could be shown that the novel polyphenol conjugate (E)-3-(3',5'-Dimethoxyphenyl)-1-(2'-methoxyphenyl)prop-2-en-1-one (DPP-23) offers antitumor effects by the selective generation of ROS without an indication of toxicity in normal tissues in vitro and in vivo. In order to further evaluate the role of DPP-23 as a potential agent in head and neck oncology, the present study investigated its cytotoxic effects on well-established HNSCC cell lines such as HLaC 78 and FaDu, as well as primary human bone marrow stem cells (hBMSCs) and human peripheral blood lymphocytes in vitro. As DPP-23 is not commercially available, it was synthesized via a 'cold' procedure of the Claisen-Schmidt condensation. Following cell treatment with DPP-23 for 24 h, viability and apoptosis were measured via a MTT assay and the Annexin V-propidium iodide test. The results suggest a dose-dependent cytotoxicity in the tested HNSCC tumor cell lines, as well as in hBMSC and lymphocytes. In contrast to previous findings, these preliminary results indicate that the cytotoxic effects of DPP-23 in benign cells may be notably greater than previously suspected. This may indicate a limitation for in the feasibility, or at least of the systemic application, of DPP-23 for patients with HNSCC

Effects of the novel polyphenol conjugate DPP-23 on head and neck squamous cell carcinoma cells in vitro

Despite partial advances in therapy for patients suffering from head and neck squamous cell carcinomas (HNSCC), prognosis still remains poor with minimal improvement in survival for over the last several decades. Some agents found are known to cause cancer cell death in vitro by promoting cellular reactive oxygen species (ROS) accumulation. This is particularly of interest as some cancer cells are more sensitive to ROS than normal cells. It could be shown that the novel polyphenol conjugate (E)-3-(3',5'-Dimethoxyphenyl)-1-(2'-methoxyphenyl)prop-2-en-1-one (DPP-23) offers antitumor effects by the selective generation of ROS without an indication of toxicity in normal tissues in vitro and in vivo. In order to further evaluate the role of DPP-23 as a potential agent in head and neck oncology, the present study investigated its cytotoxic effects on well-established HNSCC cell lines such as HLaC 78 and FaDu, as well as primary human bone marrow stem cells (hBMSCs) and human peripheral blood lymphocytes in vitro. As DPP-23 is not commercially available, it was synthesized via a 'cold' procedure of the Claisen-Schmidt condensation. Following cell treatment with DPP-23 for 24 h, viability and apoptosis were measured via a MTT assay and the Annexin V-propidium iodide test. The results suggest a dose-dependent cytotoxicity in the tested HNSCC tumor cell lines, as well as in hBMSC and lymphocytes. In contrast to previous findings, these preliminary results indicate that the cytotoxic effects of DPP-23 in benign cells may be notably greater than previously suspected. This may indicate a limitation for in the feasibility, or at least of the systemic application, of DPP-23 for patients with HNSCC

First atroposelective total synthesis of enantiomerically pure ancistrocladidine and ancistrotectorine

The first regio‐ and stereoselective total synthesis of the axially chiral 7,3′‐coupled naphthylisoquinoline alkaloids ancistrocladidine (1) and ancistrotectorine (2) has been described. Both possess a 7,3′‐coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis‐array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the “lactone method”: the two molecular halves, which were activated in an “inverse‐halogenated” form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold

5′-O-Methyldioncophylline D, a 7,8′-coupled naphthylisoquinoline alkaloid from callus cultures of Triphyophyllum peltatum, and its biosynthesis from a late-stage tetrahydroisoquinoline precursor

The natural tetrahydroisoquinoline phylline (4) was synthesized in a specifically [1,1′-13C2]-labeled form, and fed to callus cultures of Triphyophyllum peltatum. Its incorporation into naphthylisoquinoline alkaloids, among them habropetaline A (8) (as evidenced by1H,13C NMR, and 2D INADEQUATE experiments), proved 4 to be the authentic coupling substrate for the enzyme-mediated phenol-oxidative coupling with a naphthalene portion. During the feeding experiments, a new alkaloid was discovered, 5′-O-methyldioncophylline D (5). It is the first 7,8′-linked (d-type) naphthylisoquinoline isolated from a Dioncophyllaceae plant. The new alkaloid consists of two closely eluting, slowly interconverting atropo-diastereomers, (P)-5 and (M)-5. Their full absolute stereostructures were assigned, i.e., by spectroscopic and online HPLC-CD investigations

Directed synthesis of all four pure stereoisomers of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A

The first preparation of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A and its likewise naturally occurring minor atropisomer, in an atropisomerically pure form, is described. The synthesis succeeded by resolution of the already rotationally hindered, and thus atropo-diastereomeric acetamide precursors, which were then, without major loss of stereochemical information, cyclized to the respective target molecules. The strategy was applied to the first synthesis of the regioisomeric product ancistrocladinium D, likewise in a stereochemically pure form

Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius

Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyketide-derived molecular halves, followed by oxidative cyclo-condensation. Biomimetic conversion of the co-occurring 4'-O-demethylancistrocladinium A (8a) to ancistrocyclinone A (5) via a quinoid intermediate supported the postulated pathway. Ancistrocyclinone A (5) was found to significantly inhibit the viability of drug-sensitive human leukemia (CCRF-CEM) and multidrug-resistant tumor cells (CEM/ADR5000) with comparable efficacies

Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius

Two unique pentacyclic N,C-coupled naphthylisoquinolines, the ancistrocyclinones A (5) and B (6), were discovered in the Chinese liana Ancistrocladus tectorius. Furthermore, six known, likewise N,C-coupled alkaloids, viz., ancistrocladinium A (7a) and its mono- and bisphenolic analogs 8a and 9a were isolated, along with their atropo-diastereomers 7b, 8b, and 9b. The stereostructures of 5 and 6 were determined by HRESIMS, 1D and 2D NMR, oxidative degradation, and ECD calculations. The pentacyclic ancistrocyclinones A (5) and B (6) are structurally similar to berberine alkaloids - yet arising from a most different biosynthetic pathway: they are apparently formed by N,C-coupling of their polyketide-derived molecular halves, followed by oxidative cyclo-condensation. Biomimetic conversion of the co-occurring 4'-O-demethylancistrocladinium A (8a) to ancistrocyclinone A (5) via a quinoid intermediate supported the postulated pathway. Ancistrocyclinone A (5) was found to significantly inhibit the viability of drug-sensitive human leukemia (CCRF-CEM) and multidrug-resistant tumor cells (CEM/ADR5000) with comparable efficacies