Scalable Total Synthesis of Acremolactone B.

Acremolactone B is a pyridine-containing azaphilone-type polyketide with herbicidal activity. We developed an aza-6π electrocyclization-aromatization strategy to construct the tetrasubstituted pyridine ring and achieved the first total synthesis of this molecule on a gram scale. A bicyclic intermediate was expeditiously prepared by using [2 + 2] photocycloaddition and chemoselective Baeyer-Villiger oxidation, which was further elaborated to a densely substituted aza-triene. An electrocyclization-aromatization cascade was exploited to forge the tetracyclic core of the natural product, and the side chain was introduced through diastereoselective acylation and reduction.

Total Synthesis of Four Classes of Daphniphyllum Alkaloids.

The macrodaphniphyllamine-type, calyciphylline A-type, daphnilongeranin A-type, and daphnicyclidin D-type alkaloids are four structurally related classes of Daphniphyllum alkaloids. On the basis of a systematic analysis of the biogenetic network of these classes, we developed synthetic strategies centered on the C4-N and C1-C8 bonds of calyciphylline A, which took full advantage of the suitable substrates, reactions, and pathways that are altered from their counterparts in the postulated biogenetic network. Through this generalized biomimetic approach, we achieved the first synthesis of 14 Daphniphyllum alkaloids from the four subfamilies.

2-Methoxydiol derivatives as new tubulin and HDAC dual-targeting inhibitors, displaying antitumor and antiangiogenic response.

Multi-target drugs design has become an active research field because of their advantages in cancer treatment. In present study, HDAC inhibitors pharmacophore and 2-methoxyestradiol(2ME2) were combined into a new hybrid molecule for the first time. Forty-seven 2ME2 derivatives were synthesized and evaluated for antiproliferative activity. In particular, compound 4s exhibited a dual inhibition of tubulin polymerization and HDAC (IC50 = 0.06 µM toward HDAC2) activity, as well as the most potent cytotoxicity IC50 values of 0.37-4.84 µM against six cancer cell lines. Compound 4s remarkably disrupted microtubule networks, arrested cell cycle at G2/M phase, induced mitochondrial membrane potential collapse and eventually apoptosis in A549 cells. Notably, 4s was discovered to potently imped the tube-formation of HUVECs and prohibited the proliferation, migration, and invasion of HUVECs, as well as A549 cells. In addition, the anti-angiogenic and anti-metastasis activities were demonstrated via a zebrafish model test. All these beneficial anticancer activities together with its high selectivity toward noncancer cells, suggested 4s may deserves consideration for cancer therapy.

Synthesis and biological evaluation of new 2-methoxyestradiol derivatives: Potent inhibitors of angiogenesis and tubulin polymerization.

Here, we report the structural optimization of a hit natural compound, 2-ME2 (2-methoxyestradiol), which exhibited inhibitory activity but low potency on tubulin polymerization, anti- angiogenesis, MCF-7 proliferation and metastasis in vitro and in vivo. A novel series of 3,17-modified and 17-modified analogs of 2-ME2 were synthesized and investigated for their antiproliferative activity against MCF-7 and another five different human cancer cell lines leading to the discovery of 9i. 9i bind to tubulin colchicine site tightly, inhibited tubulin polymerization and disrupted cellular microtubule networks. Cellular mechanism studies revealed that 9i could induce G2/M phase arrest by down-regulated expression of p-Cdc2, P21 and cell apoptosis by regulating apoptosis-related proteins (Parp, Caspase families) in a dose-dependent manner. Importantly, 9i significantly inhibited HUVEC tube formation, proliferation, migration and invasion. The inhibitory effect against angiogenesis in vivo was confirmed by zebrafish xenograft. Furthermore, 9i could effectively inhibit the proliferation and metastasis of MCF-7 cells in vitro and in zebrafish xenograft. The satisfactory physicochemical property and metabolic stability of 9i further indicated that it can act as a promising and potent anti-angiogenesis, inhibiting proliferation and metastasis of breast cancer agent via targeting tubulin colchicine binding site.

Cyclopropyl Scaffold: A Generalist for Marketed Drugs.

In recent decades, much attention has been given to cyclopropyl scaffolds, which commonly exist in natural products and synthetic organic molecules. Clinical drug molecules with cyclopropyl rings are an area of focus in therapeutic research due to their interesting chemical properties and unique pharmacology activity. These molecular drugs against different targets are applicable in some therapeutic treatment fields including cancer, infection, respiratory disorder, cardiovascular and cerebrovascular diseases, dysphrenia, nervous system disorders, endocrine and metabolic disorders, skin disease, digestive disorders, urogenital diseases, otolaryngological and dental diseases, and eye diseases. This review is a guide for pharmacologists who are in search of valid preclinical/clinical drug compounds where the progress, from 1961 to the present day, of approved marketed drugs containing cyclopropyl scaffold is examined.

Triazol: a privileged scaffold for proteolysis targeting chimeras.

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

Concise synthesis of 2-methoxyestradiol from 17ß-estradiol through the C(sp2)-H hydroxylation.

A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17ß-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p-cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5).