Novel coumarin-piperazine-2(5H)-furanone hybrids as potential anti-lung cancer agents: Synthesis, biological evaluation and molecular docking studies.

Novel coumarin-piperazine-2(5H)-furanone hybrids 5a-l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a-l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5 l (IC50 = 11.28 µM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC50 = 202.57 µM). Moreover, hybrid 5 l (IC50 = 411.93 µM) was less toxic to WI-38 cells, with a much higher selectivity (5 l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure-activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5 l). Further, hybrid 5 l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC50 = 5.72-45.46 µM; SI ≈ 9-72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC50 = 39.07-130.82 µM; SI ≈ 0-2), showing remarkable specificity. In particular, hybrid 5 l (IC50 = 5.72 µM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5 l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5 l with CDK2 protein. Hybrid 5 l is expected to be a leading candidate for anti-lung cancer agents.

Design, synthesis and biological evaluation of rhein-piperazine-furanone hybrids as potential anticancer agents.

Novel rhein-piperazine-furanone hybrids, 5, were designed and synthesized efficiently from rhein. Cytotoxicity of all hybrids 5a-j against A549 human lung cancer cells was superior to the parent rhein and the reference cytarabine (CAR). Hybrid 5e (IC50 = 5.74 µM), the most potent compound, was 46- and 35-fold more toxic against A549 cells than rhein (IC50 = 265.59 µM) and CAR (IC50 = 202.57 µM), respectively. Moreover, hybrid 5e (IC50 = 69.28 µM) was less toxic to normal WI-38 human lung fibroblast cells with good selectivity (WI-38/A549, SI ≈ 12), being much higher than rhein (SI ≈ 1) and CAR (SI ≈ 2). Structure-activity relationship (SAR) analysis showed that cytotoxicity and selectivity against A549 lung cancer cells were greatly enhanced when methoxy-containing furanone was introduced to the hybrids (5e and 5h). Further, hybrid 5e showed better cytotoxicity against four types of human lung cancer cells (H460, A549, PC-9, and Calu-1; IC50 = 4.35-15.39 µM) than six other types of human cancer cells (SK-BR-3, SK-OV-3, 786-O, Huh-7, HCT116, and HeLa; IC50 = 13.77-60.45 µM), showing specificity. In particular, hybrid 5e showed the highest cytotoxicity (IC50 = 4.35 µM) and the highest selectivity (WI-38/H460, SI ≈ 16) against H460 human lung cancer cells. Flow cytometric analysis showed that hybrid 5e induced apoptosis in a concentration-dependent manner in H460 cells. The results show that the cytotoxicity and selectivity of rhein can be greatly enhanced by hybridization with furanone. Hybrid 5e is expected to be a leading candidate for anti-lung cancer drugs.

Design, synthesis and biological evaluation of matrine-dithiocarbamate hybrids as potential anticancer agents.

A series of novel matrine-dithiocarbamate (DTC) hybrids were efficiently synthesised from matrine through a three-step sequence involving basic hydrolysis, esterification, and DTC formation. They were evaluated for their in vitro cytotoxic potency on several human cancer and normal cells. All matrine-DTC hybrids were much more toxic against the human hepatoma cell line HepG2 than the parent matrine. Hybrid 4l (IC50 = 31.39 µM) was the most potent compound against HepG2 cells, being 156- and 3-fold more toxic than matrine (IC50 > 4900 µM) and the reference vincristine (VCR, IC50 = 93.67 µM), respectively. Moreover, hybrid 4l was less toxic to normal human embryonic kidney cell line HEK-293T, with a higher selectivity index (SI, HEK-293T/HepG2 ≈ 6) than matrine (SI ≈ 1) and VCR (SI ≈ 1). The structure-activity relationship analysis indicated that selectivity was greatly boosted when 4-(trifluoromethyl)benzyl was incorporated into the hybrids (4f and 4l). In addition, the hybrid 4l was also highly toxic to the other five types of human cancer cells (Calu-1, SK-BR-3, HUH-7, 786-O and SK-OV-3; IC50 = 44.18-112.19 µM), whereas it was relatively less toxic to the corresponding normal cells (WI-38, LX-2, HEK-293T and KGN; IC50 = 81.48-195.17 µM). Further mechanistic studies showed that hybrid 4l induced apoptosis in a concentration-dependent manner in HepG2 cells. Our results demonstrate that the cytotoxic activity of matrine can be highly enhanced by hybridisation with DTC. Hybrid 4l has promising applications in anticancer drug development.

Design, synthesis and biological evaluation of rhein-piperazine-dithiocarbamate hybrids as potential anticancer agents.

A series of novel rhein-piperazine-dithiocarbamate hybrids 3 were efficiently synthesized from rhein through a catalyst-free and one-pot, three-step sequence involving chlorination and N-acylation followed by dithiocarbamate formation. Hybrids 3 were evaluated for their in vitro cytotoxic potency by MTT assay against several human cancer and non-cancer cells. Five of the hybrids were more cytotoxic to human lung cancer cell line A549 than the parent rhein and the reference, cytarabine (CAR). Structure-activity relationship (SAR) analysis indicated that cytotoxicity was significantly enhanced when ester groups were incorporated into the hybrids (3h-j). In particular, hybrid 3h (IC50 = 10.93 µg/mL), containing a long-chain alkyl ester, was the most potent compound toward A549 tumor cells, being 7- and 5-fold more toxic than rhein (IC50 = 77.11 µg/mL) and CAR (IC50 = 49.27 µg/mL), respectively. Additionally, hybrid 3h was less toxic to the corresponding normal human lung fibroblast cell line, WI-38, with a higher selectivity index (SI, WI-38/A549 ≈ 5) than doxorubicin (DOX, SI ≈ 0), CAR (SI ≈ 2) and rhein (SI ≈ 1). Furthermore, hybrid 3h displayed more toxicity against four types of lung cancer cells (A549, Calu-1, PC-9, and H460; IC50 = 10.81-23.78 µg/mL) than against six other types of cancer cells (Huh-7, 786-O, HCT116, Hela, SK-BR-3, and SK-OV-3; IC50 = 23.85-51.98 µg/mL). Further mechanistic studies showed that hybrid 3h induced apoptosis in a concentration-dependent manner in human lung adenocarcinoma cell line PC-9. In vivo safety studies showed that hybrid 3h had no acute toxicity to the major organs of mice and did not lead to blood biochemical index changes. Our results exhibit prominent anti-cancer cell inhibition ability and no obvious systemic toxicity to normal organs, indicating that hybrid 3h has promising potential for further applications in anti-lung cancer drug development.

Design, Synthesis, and Biological Evaluation of Artemisinin-Piperazine-Phosphoramide Mustard Hybrids as Potential Anticancer Agents.

A series of novel artemisinin-piperazine-phosphoramide mustard (PPM) hybrids were designed and synthesized by incorporating phosphoramide mustard (PM) into dihydroartemisinin (DHA) via an efficient, catalyst-free two-step sequential substitution. Artemisinin-PPM hybrids showed better cytotoxic potency against HepG2 cells than both the parent DHA and the reference, vincristine (VCR). Structure-activity relationship (SAR) studies showed that the cytotoxicity was significantly enhanced by the introduction of a thiazole moiety. Hybrid 7 h, the most potent compound with the highest selectivity index IC50 (HEK-293T)/IC50 (HepG2)=16, displayed 7.4-fold stronger potency than VCR against HepG2 cells. In addition, hybrid 7 h was substantially more cytotoxic on all human cancer cells tested than on the corresponding non-cancerous cells. Flow cytometric analysis showed that 7 h significantly blocked the cell cycle in the G0/G1 phase and induced apoptosis in a concentration-dependent manner.

Synthesis of artemisinin-piperazine-furan ether hybrids and evaluation of in vitro cytotoxic activity.

For the first time, eight novel artemisinin-piperazine-furane ether hybrids (5a-h) were efficiently synthesized and investigated for their in vitro cytotoxic activity against some human cancer and benign cells. The absolute configuration of hybrid 5c was determined by X-ray crystallographic analysis. Hybrids 5a-h exhibited more pronounced growth-inhibiting action on hepatocarcinoma cell lines than their parent dihydroartemisinin (DHA) and the reference cytosine arabinoside (ARA). The hybrid 5a showed the best cytotoxic activity against human hepatocarcinoma cells SMMC-7721 (IC50 = 0.26 ± 0.03 µM) after 24 h. Furthermore, hybrid 5a also showed good cytotoxic activity against human breast cancer cells MCF-7 and low cytotoxicity against human breast benign cells MCF-10A in vitro. We found the cytotoxicity of hybrid 5a did not change when tumour cells absorb iron sulfate (FeSO4); thus, we conclude the anti-tumour mechanism induced by iron ions (Fe2+) is unclear.

Synthesis and biological evaluation of novel artemisone-piperazine-tetronamide hybrids.

For the first time, six novel artemisone-piperazine-tetronamide hybrids (12a-f) were efficiently synthesised from dihydroartemisinin (DHA) and investigated for their in vitro cytotoxicity against some human cancer cells and benign cells. All the targets showed good cytotoxic activity in vitro. Hybrid 12a exhibited much better inhibitory activity against human liver cancer cell line SMMC-7721 (IC50 = 0.03 ± 0.04 µM for 24 h) than the parent DHA (IC50 > 0.7 µM), and two references, vincristine (VCR; IC50 = 0.27 ± 0.03 µM) & cytosine arabinoside (ARA; IC50 = 0.63 ± 0.04 µM). Furthermore, hybrid 12a had low toxicity against human benign liver cell line LO2 (IC50 = 0.70 ± 0.02 µM for 24 h) compared with VCR, ARA, and DHA in vitro. Moreover, the inhibitory activity of hybrid 12a was obviously enhanced when human liver cancer cell line MHCC97H absorbed Fe2+ in vitro.

Synthesis and biological activities of artemisinin-piperazine-dithiocarbamate derivatives.

Twelve derivatives of artemisinin-piperazine-dithiocarbamate have been synthesised, and some of them showing good in vitro cytotoxic activity. Compound 3g exhibits the best inhibitory activity against SMMC-7721 cell lines with an IC50 of 0.0025 ±â€¯0.04 µM for 72 h, but the toxicity was lower against LO2 cell lines with an IC50 of 0.18 ±â€¯0.04 µM for 72 h. The results indicate that compound 3g is more cytotoxic towards cancer cell lines than towards benign cell lines compared with vincristine in vitro. And compound 3g also has good inhibitory activity against colon, breast and prostate cancer cells. Meanwhile, we have also proposed the six-member ring mechanism of DMSO in catalysing the esterification of hydroxyl and acyl chloride. Instead of using the hydroxyl, we can obtain the nucleophilic substitution production simply and efficiently without a Lewis acid, which has not been reported previously.

Synthesis and biological activities of dithiocarbamates containing 2(5H)-furanone-piperazine.

A series of new dithiocarbamates containing a 2(5H)-furanone-piperazine group was synthesized. These compounds show good in vitro cytoxic activity. Among them, compound 6c exhibits the best inhibitory activity against HeLa cell lines with an IC50 of 0.06 ±â€¯0.01 µM for 72 h, and it has good inhibitory activity against SMMC-7721 cell lines with an IC50 of 0.006 ±â€¯0.04 µM for 72 h, but the toxicity was lower against LO2 cell lines with an IC50 of 45.76 ±â€¯0.01 µM. The result showed that compound 6c is far more cytoxic towards cancer cell lines than towards benign cell lines compared with cytosine arabinoside (ARA) in vitro.

Enantioselective synthesis of Amaryllidaceae alkaloids (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine.

Cat. on a hot tin roof: Enantioselective catalytic Michael addition of α-cyanoketones to acrylates under bifunctional organocatalysis was used to construct the unique arylic all-carbon quaternary stereocenter, which is synthetically crucial in the chemical synthesis of optically pure cis-aryl hydroindole alkaloids. The protocol offers an asymmetric route to (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine.

Formal synthesis of (±)-morphine.

The pain ends here: A novel synthetic strategy for the construction of (±)-morphine rings B and E was developed, in which SmI2 -promoted reductive coupling/desulfurization and tandem alcoholysis/oxa-Michael addition featured as the key steps for the assembly of the C9-C14 and C5-O bonds, respectively. Asymmetric tandem alcoholysis/oxa-Michael addition was also feasible for the enantiocontrolled synthesis of morphine.

Toward the total synthesis of palhinine A: expedient assembly of multifunctionalized isotwistane ring system with contiguous quaternary stereocenters.

The stereoselective, expedient assembly of the key functionalized isotwistane (bridged tricyclo[4.3.1.0(3,7)]decane) system, 5/6/6 ring, with contiguous quaternary stereocenters in Lycopodium alkaloid palhinine A and its analogues via an intramolecular Diels-Alder strategy is described.

Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing gamma-butenolide moiety and preliminary evaluation of in vitro anticancer activity.

A new series of chiral 1,3,4-thiadiazoles derivatives possessing gamma-substituted butenolide moiety were synthesized and evaluated for in vitro anticancer properties. All the compounds showed good anticancer activities against Hela cell lines. Of all the studied compounds, compound 9e exhibited the best inhibitory activity with an IC(50) of 0.9 microM. After being treated with 0.1 microg/mL compound 9e for 24h, the growth inhibition rate of Hela cell lines was 59.2%.