Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent.

A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 µM) and PC-3 (IC50: 5.9 µM) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 µM. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.

Tellurophene-Containing Core-Modified Pentaphyrin(2.1.1.1.1)s.

Various core-modified tellurophene-containing pentaphyrin(2.1.1.1.1)s were synthesized via (3 + 2) condensation of 16-telluratripyrrane with different heterodiols under mild acid catalyzed conditions in 5-12% yields. The formation of pentaphyrin (2.1.1.1.1) with a N2O2Te core was not successful due to its inherent instability. The new pentaphyrins were characterized and studied by HR-MS, 1D and 2D NMR, X-ray crystallography for one of the pentaphyrins, absorption and DFT/TD-DFT techniques. The NMR studies indicated their nonaromatic nature. The X-ray structure obtained for pentaphyrin(2.1.1.1.1) with N4Te core revealed that the macrocycle exists in a highly distorted nonplanar structure. The DFT studies showed that the macrocycles are nonaromatic and exists in highly distorted nonplanar geometry. Furthermore, as the core heterocyclic groups at ethene moiety were changed from pyrrole to furan to thiophene to benzene, the macrocycles tended toward more planar structures. The absorption spectra of pentaphyrins showed one strong sharp band in the region of 450-540 nm along with a broad band in the region of 700-800 nm. The pentaphyrin(2.1.1.1.1) with N4Te core upon protonation showed distinct color change in solution and large bathochromic shifts in absorption bands with an absorption in the NIR region.

Switching of Aromatic Free Base Triphyrin(2.1.1) to Antiaromatic Phosphorus(V) Complexes of Triphyrin(2.1.1).

The aromatic 14π meso-tetraaryl triphyrin(2.1.1)s were switched to stable antiaromatic 16π P(V) complexes of triphyrin(2.1.1) by refluxing free base triphyrin(2.1.1)s with PCl3 in a mixture of solvents toluene/triethylamine for 4 h. The P(V) triphyrin(2.1.1)s were characterized by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy and their properties were studied in detail by absorption, electrochemical, and density functional theory (DFT) studies. The studies suggested that PCl3 reduces 14π triphyrins to 16π triphyrins, which were then complexed to form stable antiaromatic P(V) complexes.

Core-Modified Pentaphyrins(2.1.1.1.1) and Bis(difluoroborane) Complex: Synthesis, Structure, and Spectral and Redox Properties.

A series of hetero analogues of pentaphyrins(2.1.1.1.1) such as oxapentaphyrins(2.1.1.1.1) and thiapentaphyrins(2.1.1.1.1) were synthesized by 3 + 2 condensation of dipyrroethenedicarbinol with 16-oxatripyrrane/16-thiatripyrrane under mild acid-catalyzed reaction conditions. The stable macrocycles are freely soluble in organic solvents, and their identities were confirmed by a corresponding molecular-ion peak in high-resolution mass spectrometry, 1D and 2D NMR spectroscopy, and X-ray structure obtained for one of the oxapentaphyrin(2.1.1.1.1) macrocycles. The crystal structure and NMR studies indicated that the heterocyclic ring, such as furan in oxapentaphyrins(2.1.1.1.1) and thiophene in thiapentaphyrins(2.1.1.1.1), was inverted. In absorption spectra, the macrocycles showed one sharp band at ∼516 nm and one broad band at ∼744 nm. The spectral and X-ray studies supported the nonaromatic nature of these macrocycles. This is in contrast to the recently reported aza analogue of pentaphyrins(2.1.1.1.1), which showed antiaromatic behavior. Upon protonation, the core-modified pentaphyrins(2.1.1.1.1) macrocycles exhibited bathochromically shifted absorption bands with a distinct change in the color of the solution. The 1H NMR, nucleus-independent chemical shift, and anisotropy-induced current density studies indicated the presence of Mobius aromaticity in the protonated macrocycles. The core-modified pentaphyrins(2.1.1.1.1) can act as good coordinating ligands, as shown here by synthesizing a bis(difluoroborane) complex of one of the thiapentaphyrins(2.1.1.1.1).

Covalently linked meso-tetraaryl triphyrin(2.1.1)-ferrocene(s) conjugates: synthesis and properties.

Functionalized meso-tetraaryl triphyrins(2.1.1) containing two meso-iodophenyl groups or a bromo group at the ß-pyrrole carbon were synthesized over a sequence of steps. The covalently linked conjugates such as a triphyrin(2.1.1)-(ferrocene)2 triad and a triphyrin(2.1.1)-ferrocene dyad were obtained in 47-51% yields by coupling the appropriate functionalized triphyrin with ethynylferrocene under mild Pd(0) coupling reaction conditions. The functionalized triphyrins(2.1.1) and their conjugates were thoroughly characterized by HR-mass spectrometry and 1D and 2D NMR spectroscopy. The absorption, electrochemical and DFT studies suggested weak interactions between the triphyrin(2.1.1) and ferrocenyl moieties in triads but relatively strong interactions in dyads.

Synthesis of meso-Tetraaryl Triphyrins(2.1.1).

A simple, straightforward [2+1] condensation of 5,6-diaryldipyrroethene dicarbinols with pyrrole under mild acid-catalyzed conditions resulted in the formation of highly desirable aromatic ß-free meso-tetraaryl [14]triphyrins(2.1.1) in 15-18% yields. The triphyrins(2.1.1) are very novel monoanionic tridentate ligands that form metal complexes readily as demonstrated here by preparing Re(I) complexes.