An efficient synthesis of microtubule-stabilizing agent ceratamine A analogues is described. The key step is the application of either reductive Heck reaction or Heck reaction to construct the imidazo[4,5-d]azepine core. Thirteen novel analogues of ceratamine A were synthesized and evaluated for their in vitro cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, A549 and A2780). It was the first report about the systematic structural modification and SARs study of ceratamine A. The results demonstrated that bulky substituents at C-14 and C-16 could enhance the cytotoxicy and modification at N-7 was crucial for high potency. Especially compound 1f bearing methyl group at C-14 and C-16, and compound 1k bearing benzyl group on N-7, showed better cytotoxicy than ceratamine A against A549.Download high-res image (139KB)Download full-size image

•Bistetrahydrocarboline skeleton and its twenty derivatives were prepared.•Compound 14 and 30 showed cytotoxicity with the IC50 values at the level of 10−8 M.•Molecular docking of compound 30 indicated it bound to minor groove of DNA duplex.A novel bistetrahydrocarboline heptacyclic skeleton and its twenty derivatives were prepared from l-tryptophan through a 15-step stereospecific route. The cytotoxicities of these compounds were tested against six human cancer cell lines including HCT-116, HepG2, BGC-823, MCF-7, A2780, and HT-29. Most of the derivatives with amide side chain exhibited the IC50 values at the level of 10−7 M, and a preliminary structure-activity relationship (SAR) was discussed. Both compound 30 with 2-pyridine amide side chain and compound 14 with phthalamide side chain showed the most potent and broad cytotoxicity towards all six cell lines with the IC50 values at the level of 10−8 M. Molecular docking of compound 30 indicated it bound to minor groove of DNA duplex.Download high-res image (101KB)Download full-size image

•A series of novel tetrahydroisoquinoline-C-aryl glucosides were synthesized.•They were evaluated for the inhibition of human SGLT2.•The structure-activity relationship was discussed.•Compound 13h exhibited equivalent in vitro inhibitory activity with dapagliflozin.A series of novel tetrahydroisoquinoline-C-aryl glucosides has been synthesized and evaluated for the inhibition of human SGLT2. Compared with dapagliflozin, compound 13h exhibited equivalent in vitro inhibitory activity against SGLT2, which might become a promising candidate for the treatment of type 2 diabetes.

The total synthesis of (±)-parthenolide and (±)-7-epi-parthenolide starting from readily available limonene has been achieved with high stereoselectivity. The key synthetic features include (i) a ring expansion reaction, Oxy-Cope rearrangement to construct the medium-sized carbocycle on large scale and (ii) substrate-controlled stereoselective introduction of the lactone and epoxy moiety at a late stage, providing a flexible method to synthesize PTL analogs.

(−)-Renieramycin G, a marine antitumor natural product, is a typical member of the bis-tetrahydroisoquinoline alkaloid family. In this paper, an efficient protocol of asymmetric total synthesis of its three stereoisomers, (+)-renieramycin G, 11,13-epi-(+)-renieramycin G and 11,13-epi-(−)-renieramycin G was established by the use of a combination of l- and/or d-tyrosine as the starting materials. The preliminary cytotoxicity assays tested on human cancer cell lines revealed that the L-shaped topological configuration of (−)-renieramycin G played a critical role in its cytotoxic activity.

Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin–ecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from l-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines including HCT-8, BEL-7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these compounds exhibited potent antitumor activity, and a preliminary structure–activity relationship (SAR) was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity against MDA-MB-231 cell line with the IC50 value of 50 nM.Graphical abstractTwenty four simplified saframycin–ecteinascidin derivatives were synthesized. The cytotoxic activities of these compounds were screened and the structure–activity relationship was discussed.Highlights► Twenty-four simplified saframycin–ecteinascidin analogs were prepared. ► Their structures were confirmed through NMR and HRMS. ► Their cytotoxicity were screened. ► Most compounds showed potent cytotoxicity.

A series of novel dinuclear platinum(II) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized as potential anticancer agents in several steps starting from commercially available l-DOPA. The cytotoxicities of the series of dinuclear platinum(II) complexes of tetrahydroisoquinoline were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. These complexes showed selective inhibition activity against cisplatin-insensitive cell line Skov3.A series of novel dinuclear platinum(II) complexes with (1S, 3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized and their cytotoxicity were screened.

The total synthesis of ceratamine A, a natural microtubule-stabilizing agent with unusual cellular effects, has been accomplished starting from 5-methoxybenzimidazole in 10 steps in an overall yield of 12.7%. The key steps in the synthesis involved the Schmidt rearrangement to construct the azepine ring, the alkylation of lactam to introduce the C-5 benzylic side chain, and the highly economical SNAr reaction to install the C-2 methylamine residue.

(−)-Saframycin A and its nineteen analogues were prepared from l-tyrosine in 24 steps, and their structures were confirmed through NMR and HRMS. The cytotoxicities of these compounds were tested against HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-803, Hela, HELF and KB cell lines. The IC50 values of the cytotoxicity of most compounds were at the level of nM. Compound 7d with 2-furan amide side chain showed the most potent cytotoxicity of all these compounds with an average IC50 value of 6.06 nM.(–)-Saframycin A and its nineteen analogues were prepared from L-tyrosine in 24 steps. The cytotoxic activities of these compounds were screened and the structure–activity relationship was discussed.Highlights► (−)-Saframycin A and its nineteen analogues were prepared. ► Their structures were confirmed through NMR and HRMS. ► The cytotoxicity were screened. ► Most compounds showed potent cytotoxicity. ► The structure–activity relationship has been discussed.

A series of novel N-methylbisindolylmaleimides and natural amino acid conjugates were synthesized and evaluated for their inhibitory activity against six tumor cell lines. Most of the compounds exhibited moderate in vitro cytotoxic activities in the range of 10–100 μmol/L.

A series of novel cisplatin-type platinum complexes with (1S,3S)-1,2,3,4-tetrahydroisoquinolines as the ligands were synthesized as potential anticancer agents in several steps starting from commercially available l-DOPA. The cytotoxicities of these compounds were tested against HCT-8, BEL-7402, A2780, MCF-7, Hela, A549 and BGC-823 cell lines by the MTT test. Some compounds exhibited better cytotoxic activity than cisplatin. The structure–activity relationship has been revealed.A series of novel cisplatin analogues were designed and synthesized. Some compounds exhibited better cytotoxic activity than cisplatin. The structure–activity relationship was revealed.Research highlights► Eighteen novel cisplatin-type platinum complexes were synthesized. ► The substitution effect was studied. ► The cytotoxicities of these compounds were screened. ► Some compounds exhibited better cytotoxic activity than cisplatin. ► The structure–activity relationship has been revealed.

(−)-Renieramycin G and fifteen C-22 analogs were prepared employing l-tyrosine as the chiral starting material. These analogs, along with (−)-renieramycin G itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, A2780, MCF-7, A549, BGC-823, Ketr3, KB, Hela cells. The IC50 values of most of these analogs were at the level of μM. Among these analogs, 2-thiophenecarboxylate ester derivative 17 exhibited potent cytotoxic activity against KB cell line with the IC50 of 20 nM. From this study, it could be concluded that the C-22 side chain played an important role in the cytotoxic potency and specificity of this class of (−)-renieramycin G derivatives.

A novel series of N-methylbisindolylmaleimides derivatives bearing 2-acetamino acid moieties were synthesized. The cytotoxic activities of these compounds were tested in six tumor cell lines. The most potent compound 8d displayed cytotoxicity against six human tumor cell lines in the micromolar range.A novel series of N-methylbisindolylmaleimides derivatives bearing 2-acetamino acid moieties were synthesized. The most potent compound 8d displayed cytotoxicity against six human tumor cell lines in the micromolar range.

A highly effective, new chiral 1,2,3,4-tetrahydroisoquinoline catalyst 1 for the diethylzinc addition to aryl aldehydes has been investigated. Using 10 mol% of this chiral catalyst, secondary alcohols can be obtained in up to 87% yield and 99.5% ee under mild conditions.

Optically active 3-butylphtalide of high enantiomeric excesses (up to 93% e.e.) was synthesized from the reduction of o-pentanoylbenzoic ester with borane using B-methyloxyoxazaborolidine (1b) as the chiral catalyst.