Five novel iridal-type triterpenoid derivatives, including three unprecedented adducts of spiroiridal and isoflavonoid, named belamcandanins A–C (1–3), one unprecedented iridal lactone, named belamcanolide A (4), and one new and rare iridal epoxide, named belamcanoxide A (5), have been isolated from the rhizomes of Belamcanda chinensis, along with five known compounds. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 1–3 represent the first meroterpenoids composed of an isoflavonoid linked to a spiroiridal-triterpenoid. To the best of our knowledge, compound 4 is the first example of 5/6-fused bicyclic iridal lactone. Compounds 1–8 were evaluated for their in vitro cytotoxicity against five tumor cell lines. Among them, compounds 5–8 showed moderate cytotoxic activities against five cancer cell lines with IC50 values from 3.26 to 8.63 μM.

Six new iridal-type triterpenoids containing an unprecedented cyclopentane ring, polycycloiridals E–J (1–6), were isolated from a large-scale re-extraction of Iris tectorum. A possible biosynthesis pathway is postulated. The known spirioiridotectal D (7) was also obtained in the current investigation, and its structure was unequivocally defined using X-ray diffraction data. Compound 7 suppressed LPS-activated NO production in the BV2 cell line with an IC50 value of 0.54 μM.

Nine new iridoid glycosides, rehmachingiiosides A–I (1–9), together with 16 known analogues, were isolated from the whole plants of Rehmannia chingii. The structures of compounds 1–9 were elucidated on the basis of spectroscopic data analysis and from chemical evidence. Furthermore, in two vitro assays, compounds 5 and 10 showed an inhibitory effect on LPS-induced NO production with IC50 values of 2.5 and 7.3 μM, and compounds 4, 6, and 10–12 (when evaluated at 10 μM) exhibited evidence of hepatoprotective effects against APAP-induced HepG2 cell damage.

•Steroidal hybrids 12a–x were synthesized and showed varied cytotoxicity against the tested cancer cell lines.•Compounds with terminal isatin scaffold were sensitive to SH-SY5Y cells possibly through LSD1 inactivation.•Compound 12g potently inhibited growth of SH-SY5Y cells (IC50 = 4.06 μM).•Compound 12g arrested cell cycle at G2/M phase, induced apoptosis and decreased MMP.•Docking simulations were performed to show the binding models of compound 12g in the active site of LSD1.A series of steroidal hybrids with different terminal bioactive scaffolds were synthesized using the molecular hybridization approach and further evaluated for their antiproliferative activity against several cancer cell lines of different origins using the MTT assay. The preliminary results indicated that compounds 12a–h with the terminal isatin motif were remarkably sensitive to SH-SY5Y cells, thereby exerting potent growth inhibition in vitro. This selectivity is possibly attributed to LSD1 inactivation (IC50 = 3.18 μM). Besides, we also found that the chloro atom at the 7-position on the isatin core was beneficial for the activity through the SARs studies. Among this series, compound 12g showed the best inhibitory activity (IC50 = 4.06 μM) against SH-SY5Y cells, which was comparable to that of 5-FU. Compound 12g arrested cell cycle at G2/M phase, induced apoptosis accompanied with decrease of mitochondrial membrane potential, and inhibited LSD1 potently (IC50 = 3.18 μM). Docking studies showed that compound 12g formed interactions with surrounding amino acid residues and the steroid nucleus occupied the tubular hydrophobic cavity of the active site. Compounds 13–18 represented weak to moderate activity against the tested cancer cell lines. The steroidal dimer 20 and the structurally simplified non-steroidal dimer 21 were found to be devoid of the inhibitory activity.Steroidal hybrids were synthesized and evaluated for their antiproliferative activity. Compound 12g potently inhibited growth of SH-SY5Y cells possibly through the inactivation of LSD1, arrested cell cycle at G2/M phase, induced apoptosis and decreased MMP. Docking simulations were performed to rationalize the potency toward LSD1.

•Three new iridal metabolites, iridojaponal A-C were isolated from Iris japonica.•Iridojaponal A-B are the first examples of degraded iridals containing 16 carbons.•The absolute configuration at C-22 of 3 was determined by CD analysis.•Compounds 1 and 2 exhibited moderate hepatoprotective activities.Three new iridal metabolites, iridojaponal A (1), B (2) and iridojaponal C (3) were isolated from the whole plants of Iris japonica. Their structures were elucidated on the basis of comprehensive spectroscopic data and chemical evidence. Iridojaponal A (1) and B (2) are the first examples of degraded iridals containing only 16 carbons. A plausible biogenetic pathway of 1 and 2 was also proposed. The absolute configuration at C-22 of 3 was determined by CD analysis accordance with Snatzke’s method. Furthermore, In vitro bioactivity assays, compounds 1 and 2 exhibited moderate hepatoprotective activities against APAP-induced HepG2 cell damage at a concentration of 10 μM.

•Four new triterpenoid saponins, schekwangsiensides H–K were reported.•Inhibitory activities against FBPase1 of the triterpenoid saponins were reported.•Compounds 3, 8, 17, and 18 exhibited weak inhibitory activities against FBPase1.Four new triterpenoid saponins, schekwangsiensides H–K (1–4) were isolated from the aerial parts of Schefflera kwangsiensis, together with fifteen esters (5–19) of known saponins. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 3, 8, 17, and 18 exhibited weak inhibitory activities against fructose-1,6-bisphosphatase (FBPase1).

•Two new lupane saponins, Schekwanglupaside A and B were reported.•Hepatoprotective activities of compounds 1–5 were evaluated.•Compounds 2 and 4 exhibited moderate hepatoprotective activities.Two new lupane saponins, Schekwanglupasides A and B (1 and 2), together with three esters (3–5) of known lupane saponins were isolated from the aerial parts of Schefflera kwangsiensis. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 2 and 4 (10 μM) exhibited moderate hepatoprotective activities against d-galactosamine-induced HL-7702 cell damage.

•Spirooxindoles are promising scaffolds in drug discovery.•CFI-400945 has entered phase І clinical trials for cancer therapy.•The kinase selectivity of CFI-4009345 needs to be further explored.The identification of novel anticancer agents with high efficacy and low toxicity has always been an intriguing topic in medicinal chemistry. The unique structural features of spirooxindoles together with diverse biological activities have made them promising structures in new drug discovery. Among spirooxindoles, CFI-400945 holds its promise as the first potent PLK4 inhibitor, the fumarate of CFI-400945 has entered phase I clinical trials for the treatment of solid tumors. However, questions remain as to whether PLK4 is the only relevant therapeutic target for CFI-400945. To highlight this significant progress of CFI-400945 in last two years, this review centers on the identification from a focused kinase library, structural optimizations and strategies involved, structure-activity relationships, modes of action, target validation, chemical synthesis and, more importantly, the kinase selectivity between PLK4 and other targets.The ELISA assay of a focused kinase library yielded the indolinone as PLK4 inhibitor. Extensive modifications generated CFI-400945, which has entered phase I clinical trials for cancer therapy. However, the kinase selectivity is the major concern that needs to be further investigated.

•Eleven new oleanane-type triterpenoid saponins were reported in this paper.•A high resolution mass spectrometry was used to determine artifacts.•Hepatoprotective activities of the twenty compounds were reported.•The methods of extracting compounds with glucuronic acid were discussed.Eleven new oleanane-type triterpenoid saponins were isolated from the aerial parts of Schefflera kwangsiensis (1–11), together with nine esters (12–20) of known saponins. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 2, 3, 5, 7, 8, 11–13, 15, 17 and 18 (10 μM) exhibited moderate hepatoprotective activity against d-galactosamine-induced HL-7702 cell damage.

Seven new iridals (1–7), designated as iritectols C–F, 22-epiiritectol D, 22-epiiritectol E, 22-epiiritectol F together with three known analogues were isolated from the rhizomes of Iris tectorum. Among them, compounds 2 and 3, 4 and 5, and 6 and 7 were found to be three pairs of C-22 epimers, some of which were separated by chiral column chromatography. This is the first report on the occurrence of epimers of monocyclic iridals. Their structures were elucidated on the basis of extensive spectroscopic analysis. The isolates were evaluated for their cytotoxic activities against five human tumor cell lines. Compound 1 but not others exhibited moderate cytotoxic activities, with IC50 values ranging from 4.1 to 9.8 μM. The structure–activity relationship of the tested compounds was briefly discussed.

Six novel iridal-type triterpenoids with a previously unreported 3,6-dihydro-2H-pyran moiety, named spirioiridotectals A–F (1–6), were isolated from the ethanol extract of the rhizomes of Iris tectorum. Their structures were elucidated on the basis of extensive spectroscopic analysis. Furthermore, in in vitro bioactivity assays, compounds 1, 2, and 6 exhibited neuroprotective activities against serum-deprivation-induced PC12 cell damage.

•Compound 3 was efficiently synthesized in two steps.•Compound 3 exhibited broad-spectrum cytotoxic activity and was more potent than 5-Fu.•Compound 3 showed low toxicity against L-02.•Compound 3 showed cell cycle arrest at G2/M phase and induced apoptosis.A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer was designed, synthesized and evaluated for its cytotoxic activity against five human cancer cell lines and the cytotoxicity against human normal liver cell L-02. Compound 3 showed excellent cytotoxic activity and good selectivity between cancer and normal cells. Further mechanistic studies revealed that treatment of EC109 cells with compound 3 caused an obvious G2/M arrest in a concentration- and time-dependent manner and induced apoptosis probably through the mitochondrial pathway accompanied with the decrease of mitochondrial membrane potential, activations of caspase-9/-3, cleavage of MDM2 as well as up-regulation of the expressions of p53 and Bax.Compound 3 showed excellent cytotoxic activity against five human cancer cell lines (IC50 < 3.2 μM) and low toxicity against L-02 and induced G2/M arrest and apoptosis probably through the mitochondrial pathway.

•Two series of novel steroidal dienamides were synthesized.•All these compounds exhibited broad-spectrum cytotoxic activities.•Most of them were more potent than 5-Fu against five human cancer cell lines.•Compounds 4j and 4k were highly selective in their cytotoxic activities.•Compound 4c showed cell cycle arrest at G2/M phase and induced early apoptosis.Two series of steroidal dienamides 4a–q and 5a–f were designed, synthesized and evaluated for cytotoxic activities against five human cancer cell lines (MGC-803, EC109, PC-3, SMMC-7721 and MCF-7). The protocol developed efficiently achieved the construction of carbon–carbon double bond and selective conversion of nitrile group into carboxamide in one-pot procedure. Besides, compounds 4a–q and 5a–f showed moderate to excellent cytotoxic activities with the IC50 values ranging from 0.1 to 40 μM and most of them were more potent than 5-fluorouracil. Particularly, four compounds 4d, 4e, 4q and 5a showed excellent selectivity against MGC-803 with the IC50 values less than 1 μM. Flow cytometry analysis demonstrated that compound 4c caused the cellular early apoptosis and cell cycle arrest in G2/M phase in a concentration-independent manner.All the compounds showed moderate to excellent cytotoxic activities against five human cancer cell lines. Four compounds showed excellent selectivity against MGC-803 (IC50 < 1 μM). Compound 4c induced G2/M arrest and early apoptosis.

A new one-step synthesis of 3-hydroxymethylbenzofuran, based on intramolecular cyclization of 2-(methoxymethyl)-2-(2′-methoxymethyl-4′-methylphenyl)-butanone 1 under diluted hydrochloric acid in THF, was developed. The mechanism for this process was investigated via chemical equilibrium shift of tautomer in acidic conditions. The applicability of this new method was studied further in this paper.A new method for the synthesis of 3-hydroxymethylbenzofuran derivatives was developed. The mechanism for this process was investigated and realized via chemical equilibrium shift of tautomer in acidic condition.

Eight new sesquiterpenes (1–8) and one new norsesquiterpene (9) named calamusins A–I were isolated from the ethanol extract of Acorus calamus rhizomes. The absolute configuration of compound 8 was determined by comparing its experimental and calculated ECD spectra. The absolute configurations of the other compounds were determined from their CD spectra. Furthermore, in in vitro assays, compounds 3, 4, 7, and 9 (10 μM) exhibited weak hepatoprotective activities against APAP-induced HepG2 cell damage.

Eleven new iridoid glycosides, rehmaglutosides A–K (1–11), together with 20 known analogues were isolated from the air-dried roots of Rehmannia glutinosa. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 3, 7, and 9–11 (10 μM) exhibited moderate hepatoprotective activities against d-galactosamine-induced HL-7702 cell damage.

An unexpected reduction of dimethyl pyridine-2,3-dicarboxylate to 1,2,3,4-tetrahydrofuro[3,4-b]pyridin-5(7H)-one with sodium borohydride in ethanol and tetrahydrofuran, respectively, is described, a hypothetic mechanism for the unusual reductive product is proposed.

A novel peptide designated secapin-1, was purified and characterized from Apis mellifera. The molecular weight of 25 amino acid peptide secapin-1 was found to be 2821.5625 Da by ESI-FTICR-MS. It showed high identity to secapin. The sequence of secapin-1 was determined to be YIINVPPRCPPGSKFVKNKCRVIVP by automatic Edman degradation. A disulfide bond was formed between Cys9 and Cys20 residues. In addition, an analogue of secapin-1 was synthesized by solid phase peptide synthesis method. The synthesis product was successfully purified and identified to homogeneity by using a combination of SEC, IEC, and RP-HPLC techniques.

Seven oleanane-type triterpenoid saponins, named clethroidosides A–G (1–7), an ursane-type triterpenoid saponin, clethroidoside H (8), and six known saponins were isolated from the aerial parts of Lysimachia clethroides. The structures of the saponins were elucidated on the basis of physical data analysis (1D and 2D NMR, HR-ESIMS) and chemical evidence. The cytotoxic activities of compounds 1–14 were evaluated against five human tumor cell lines (HT-29, HePG2, BGC-823, A549, and A375). Compounds 3, 4, 6, and 11–13 exhibited moderate cytotoxic activity, with IC50 values of 0.75–2.62 μM, while compound 5 showed selective cytotoxic activity.

Three novel sesquinlignans, tatanans A (1), B (2), and C (3), have been isolated from the rhizomes of Acorus tatarinowii Schott. Their structures were established by spectroscopic techniques and single-crystal X-ray analysis. Tatanans A−C potently increase GK enzymatic activity with EC1.5 values in the range of 0.16−1.85 μM. The potent GK activity and unique structural features of tatanans make them promising leads for therapeutic development of antihyperglycemic drugs.

Four new 2-arylbenzofuran derivatives, cathafurans A (1), B (2), C (3), and D (4), were isolated from the stem bark of Morus cathayana. Their structures were determined by spectroscopic methods. Compounds 2 and 3 exhibited moderate activities against five human cancer cell lines, with IC50 values ranging from 6.17 to 9.60 μg/mL.

A new method for preparing (2Z, 4Z, 6Z)-4,5-diethyloxepinedicarboxylate by one-step is described. The synthesis of several oxepines and azepines derivatives was carried out by the reaction of substituted furans or pyrroles with diethyl acetylenedicarboxylate in boiling toluene. The effect factors for this reaction were discussed and reaction condition was optimized.

•Spirooxindoles are privileged scaffolds in drug discovery.•A series of novel steroidal spirooxindoles were synthesized.•Most of these compounds exhibited moderate to good antiproliferative activity.•Some of them were more potent than 5-FU.•Compound 3d caused cell cycle arrest at G2/M phase and early apoptosis.A series of novel steroidal spirooxindoles 3a–h were synthesized from pregnenolone in a high regioselective manner using the 1,3-dipolar cycloaddition as the key step. This protocol resulted in the formation of two C–C bonds, one C–N bond and the creation of one pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spirooxindoles exhibited moderate to good antiproliferative activity against the tested cell lines and some of them were more potent than 5-FU. Among them, compounds 3e and 3f displayed the best antiproliferative activity against MCF-7 cells with the IC50 values of 4.0 and 3.9 μM, respectively. Flow cytometry analysis demonstrated that compound 3d caused the cellular apoptosis and cell cycle arrest at G2/M phase in a concentration-dependent manner. Docking results indicated that compound 3d fitted well into the MDM2 active site 1RV1 by interacting with Lys94 and Thr101 residues.Download full-size image

•A new class of steroidal pyran–oxindole hybrids were efficiently synthesized in one pot.•These compounds were more sensitive to MCF-7 and MGC-803 cells.•Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells.•Compound 4f showed excellent cytotoxicity against T24 cells (IC50 = 4.43 μM).•Compound 4i showed cell cycle arrest at G2/M phase and induced early apoptosis.A series of novel steroidal pyran–oxindole hybrids were efficiently synthesized in a single operation through the vinylogous aldol reaction of vinyl malononitrile 3 with substituted isatins involving the construction of C–C and C–O bonds. Some compounds displayed moderate to good cytotoxicity against T24, SMMC-7721, MCF-7 and MGC-803 cells. Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells with the IC50 values of 4.43 and 8.45 μM, respectively. Further mechanism studies indicated that compound 4i induced G2/M arrest and early apoptosis in a concentration- and time-dependent manner.Graphical abstractDownload full-size image

•The steroidal dienamides were synthesized stereoselectively through a cascade aldol/cyclization process.•These compounds had moderate to excellent cytotoxic activities.•Some of these compounds were more potent than 5-fluorouracil.•Compound 3c represented excellent inhibition against MCF-7 (IC50 = 0.76 μM).The stereoselective and metal-free protocol involving a cascade aldol/cyclization process for the synthesis of steroidal (E, E) dienamides from steroidal α, α-dicyanoalkene was reported. This protocol efficiently achieved the construction of CC bond and selective conversion of cyano group into carboxamide in one-pot procedure under mild condition. Further biological evaluation showed that some of these compounds had moderate to excellent cytotoxic activities against all the tested cancer cell lines and were more potent than well-known drug 5-fluorouracil. Particularly, compound 3c represented excellent inhibitory effect against MCF-7 (IC50 = 0.76 μM), which was about 10-fold more potent than 5-fluorouracil.Download full-size image

A simple and practical method for synthesis of the D-ring modified steroidal dienamides (4a–k) from the steroidal α,α-dicyanoalkene 3 and aldehydes via vinylogous aldol reaction was first reported. By using NaOAc as a base, the desired products were obtained in moderate to good yields in ethanol under mild conditions. All the synthesized steroidal dienamides are new and are currently being evaluated for their biological activities.Graphical abstractDownload full-size imageHighlights► Steroidal dienamides were first synthesized in moderate to good yields under mild conditions. ► Aldehydes reacted with steroidal α,α-dicyanoalkene to give the Steroidal dienamides. ► All the products were obtained via rearrangement of 2H-pyrans catalyzed by NaOAc.

Four new aristolochic acid derivatives aristchamic A (1), aristchamic B (2), aristochamic C (3a), aristchamic D (3b) and one new aristolactam aristolactam-CV (4), together with 10 known compounds (5–14), were isolated from the rhizomes of Aristolochia championii. Their structures were assigned by detailed analysis of MS and NMR spectroscopic data. All of the isolated compounds were evaluated for their cytotoxic activities against HCT-116, HepG2, BGC-823, NCI-H1650, and A2780 cell. Compound 1 exhibited significant cytotoxic activity against HCT-116, HepG2, BGC-823, and NCI-H1650, with IC50 values of 0.50, 7.37, 2.66, and 0.75 μM, respectively.Download high-res image (231KB)Download full-size image

Polycycloiridals A–D, four novel iridals with an unprecedented α-terpineol moiety resulting from cyclization of the homofarnesylside chain, were isolated from the ethanol extract of rhizomes of Iris tectorum. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. The absolute configuration of 1 was determined by the modified Mosher’s method and comparison of experimental and calculated electronic circular dichroism (ECD) spectrum. A possible biosynthetic pathway was postulated.