New Members of the Centrapalus Coumarin and Pauciflorin Series from Centrapalus pauciflorus.

Monoterpene and 5-methylcoumarin- or 5-methylchromone-coupled meroterpenoids occurring mainly in the Asteraceae species proved to have high potency against protozoans, worms, and various tumor cells, which make them interesting targets for searching for new bioactive compounds. The African plant Centrapalus pauciflorus was applied in traditional medicine for healing chest pain and stomach aches. Three new meroterpenoids named centrapalus coumarin N (2), pauciflorins P (3), and Q (4), and the already known cyclohoehnelia coumarin (1), were isolated from the chloroform extract of C. pauciflorus, together with centrapalus coumarin O (5), which was obtained for the first time from a natural source. The structures were established from HRESIMS, 1D (1H NMR, 13C NMR JMOD) and 2D NMR (HSQC, HMBC, 1H-1H COSY, NOESY) spectroscopies, and the absolute stereochemistry of 5 was determined by single-crystal X-ray diffraction. Compounds 1, 2, and 5 are hybrid molecules of 5-methylcoumarin-monoterpene origin. Centrapalus coumarin N is the first example of meroterpenoids, where a monoterpene is fused with a coumarin and an acetophenone unit. Pauciflorins P and Q are dimeric meroterpenoid isomers. Centrapalus coumarins N and O were tested for antiproliferative activity against human adherent breast (MCF-7, MDA-MB-231), cervical (HeLa, SiHa), and ovarian (A2780) cancer cell lines, and were additionally included to obtain data concerning cancer selectivity. Both compounds exhibited moderate (IC50 > 10 µM) but selective activity against A2780 cells.

Anticancer Meroterpenoids from Centrapalus pauciflorus leaves: Chromone- and 2,4-Chromadione-Monoterpene Derivatives.

Eight previously undescribed chromones, named pauciflorins F-M and two 5-methyl-2,4-chromadione derivatives named as pauciflorins N and O, were isolated from the methanol extract of the leaves of Centrapalus pauciflorus (Willd.) H.Rob. together with the known (+)-spiro-ethuliacoumarin. The structures were determined via extensive spectroscopic analyses, including HRESIMS, 1D NMR (1H, 13C JMOD), and 2D NMR (HSQC, HMBC, 1H-1H COSY, and NOESY) experiments. Through an MTT assay, seven isolated compounds were tested for their antiproliferative properties against human adherent breast (MCF-7, MDA-MB-231), cervical (HeLa, SiHa), and ovarian (A2780) cancer cell lines. Pauciflorin F was effective against MCF-7 breast cancer cells, its activity (IC50 5.78 µM) was comparable to that of the reference agent cisplatin (IC50 5.78 µM).

Investigation of the Antineoplastic Effects of 2-(4-Chlorophenyl)-13α-Estrone Sulfamate against the HPV16-Positive Human Invasive Cervical Carcinoma Cell Line SiHa.

Cervical carcinoma is one of the most frequent malignant gynecological cancers in women of reproductive age. Because of the poor tolerability of currently available chemotherapeutic agents, efforts have been focused on developing innovative molecules, including steroids, that exert antineoplastic effects with a better safety profile. In addition to their endocrine properties, certain estrogens exhibit additional biological activities, such as antiangiogenic and anticancer effects. Based on previous studies, the antineoplastic properties of 13α-estrone sulfamate derivatives (13AES1-3) were investigated, and the mechanism of action for the most promising compound 13AES3 was explored. Based on their effects on the viability of different human adherent gynecological cancer cells, the SiHa cervical cell line was used for mechanistic experiments. The most active analog 13AES3 was shown to exert considerable proapoptotic effects, as evidenced by a colorimetric caspase-3 assay and fluorescent double staining. It also elicited antimigratory and anti-invasive effects in a concentration-dependent manner, as evidenced by wound healing and Boyden chamber assays, respectively. Regarding their mechanism of action, 13AES derivatives were shown to inhibit tubulin polymerization, and computer simulations provided a possible explanation for the importance of the presence of the chlorophenyl ring on the estrane skeleton. 13AES3 is considered to be the first 13α-estrone derivative with a significant antineoplastic potency against SiHa cancer cells. Therefore, it might serve as a valuable lead molecule for the design of anticancer agents targeting cervical carcinomas.

Pauciflorins A-E, Unexpected Chromone-Monoterpene-Derived Meroterpenoids from Centrapalus pauciflorus.

Five unusual meroterpenoids based on new carbon skeletons, pauciflorins A-E (1-5), were isolated by multistep chromatographic separations of a methanol extract of the aerial parts of Centrapalus pauciflorus. Compounds 1-3 are derived by the connection of a 2-nor-chromone and a monoterpene unit, whereas 4 and 5 are dihydrochromone-monoterpene adducts with a rarely occurring orthoester functionality. The structures were solved using 1D and 2D NMR, HRESIMS, and single-crystal X-ray diffraction. Pauciflorins A-E were evaluated for antiproliferative activity against human gynecological cancer cell lines, but were inactive (IC50 < 10 µM) in each case.

Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers.

Novel 13α-estrone derivatives have been synthesized via direct arylation of the phenolic hydroxy function. Chan-Lam couplings of arylboronic acids with 13α-estrone as a nucleophilic partner were carried out under copper catalysis. The antiproliferative activities of the newly synthesized diaryl ethers against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231, HeLa, SiHa) were investigated by means of MTT assays. The quinoline derivative displayed substantial antiproliferative activity against MCF-7 and HeLa cell lines with low micromolar IC50 values. Disturbance of tubulin polymerization has been confirmed by microplate-based photometric assay. Computational calculations reveal significant interactions of the quinoline derivative with the taxoid binding site of tubulin.

Transition metal-catalysed A-ring C-H activations and C(sp2)-C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties.

Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13α-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki-Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13α-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C-H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13α-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.

Pd-catalyzed Suzuki-Miyaura couplings and evaluation of 13α-estrone derivatives as potential anticancer agents.

13α-Estrones are of great value owing to their potent multiple bioactivity, including anticancer activity. 3-OH or 3-OBn derivatives of 2- or 4-[(subst.) phenyl]-13α-estrone as potential antiproliferative agents have been synthesized via facile, microwave-induced, Pd-catalyzed Suzuki-Miyaura coupling. 2- or 4-Halogenated 13α-estrone derivatives have been reacted with (4-subst.)phenylboronic acids using Pd(PPh3)4 as catalyst. The nature of para substituents at the introduced phenyl group did not influence the outcome of couplings. Certain newly synthesized compounds displayed substantial antiproliferative action against human adherent cancer cell lines of gynecological origin. Important structure-activity relationships were revealed, which might be helpful in the design of potent and selective anticancer derivatives based on the hormonally inactive 13α-estrane core.