Additional file 3: of Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38

MTT assay of combination of RTK inhibitors with cisplatin. Influence of 48 h preincubation with 1.5 μM NVP-AEW541, 1 μM lapatinib or a combination of both compounds on cisplatin sensitivity in HCC38. (DOCX 173 kb

Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity

3,7-Diallyl-bispidin-9-one (<b>6</b>) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]­nonan-9-one) is converted to <i>N</i>-unsubstituted spiro­[bispidin-9,2′-[1,3]­dioxolane] (<b>12</b>; 35%). The ketal crystallizes in the forms of anhydrous <b>12a</b> and the dihydrate <b>12b</b>. The molecules in anhydrous <b>12a</b> are linked to each other, forming N1–H1···N2–H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate <b>12b</b>, the ketal molecules are connected to a central string of water molecules by O3–H···O1 and O4–H···N1 hydrogen bonds, but not to themselves. Reaction of <b>12</b> with (1,5-hexadiene)­PtCl₂ affords almost quantitatively spiro­[bispidin-9,2′-[1,3]­dioxolane]­PtCl₂ (<b>13</b>). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)­PtCl₂ (<b>14</b>; 85%). Compound <b>14</b> reacts with Ag₂cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)­Pt­(cbdca)·2H₂O (<b>15b</b>), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)­Pt­(cbdca) (<b>15a</b>). Similarly, anhydrous (bispidin-9,9-diol)­Pt­(oxalate) (<b>16</b>) is obtained. Crystal structures of <b>14</b> and <b>15b</b> reveal association by various forms of O–H···O, O–H···Cl, N–H···Cl, and N–H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes <b>14</b>–<b>16</b>, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of <b>14</b>–<b>16</b> up to 316 μM was found against the noncancer cell line HEK293

Bispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin. Synthesis, Structures, and Cytotoxicity

Bispidine (3,7-diazabicyclo[3.3.1]­nonane, C₇H₁₄N₂) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C₇H₁₄N₂)­PtCl₂·DMF (<b>1b</b>), obtained from (1,5-hexadiene)­PtCl₂ and bispidine in DMF, is dimeric in the solid state. Dissolving <b>1b</b> in hot <i>N</i>-methylformamide allows crystallization of the solvent-free polymeric (C₇H₁₄N₂)­PtCl₂ (<b>1a</b>). Recrystallization of <b>1a</b>,<b>b</b> from hot water yields the trihydrate (C₇H₁₄N₂)­PtCl₂·3H₂O (<b>1c</b>). Reaction of <b>1</b> with Ag₂(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C₇H₁₄N₂)­Pt­{C₄H₆(CO₂)₂}·5H₂O (<b>2b</b>), which loses water in vacuo to give (C₇H₁₄N₂)­Pt­{C₄H₆(CO₂)₂} (<b>2a</b>). Reaction of <b>1</b> with AgNO₃ in water, followed by addition of Na₂C₂O₄, affords the water-free polymeric (C₇H₁₄N₂)­Pt­(C₂O₄) (<b>3</b>). All complexes have been structurally characterized, revealing various patterns of N–H···Cl and N–H···O hydrogen bonds. In the hydrates <b>1c</b> and <b>2b</b> the complexes are embedded in intricate three-dimensional water networks. Complexes <b>1a</b>, <b>2a</b>, and <b>3</b> have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor

A new cytotoxic steroid from co-fermentation of two marine alga-derived micro-organisms

<div><p>Bioactivity-guided chemical investigation of a co-culture of marine-derived micro-organisms has yielded one new steroid, 7β-hydroxycholesterol-1β-carboxylic acid (<b>1</b>) with an unprecedented carboxylic acid group at C-1, together with three known steroidal metabolites (<b>2</b>–<b>4</b>). The chemical structures and stereochemistry of the isolated compounds were unambiguously determined based on extensive 1D, 2D NMR and HR-ESI-MS measurements. The isolated compounds were assessed for their cytotoxic activity against four different human tumour cell lines K562 (leukaemia), HCT116 (colon), A2780 (ovary) and its cisplatin-resistant mutant (A2780 CisR), and they revealed moderate activities with IC₅₀ values ranging from 10.0 to 100.0 μM.</p></div

Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC5 with Improved Activity against Chemoresistant Cancer Cells

The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound <b>19i</b> (LMK235) (<i>N</i>-((6-(hydroxyamino)-6-oxohexyl)­oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of <b>19i</b> in comparison to vorinostat or trichostatin A (TSA). <b>19i</b> shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range

Multicomponent Synthesis and Binding Mode of Imidazo[1,2‑<i>a</i>]pyridine-Capped Selective HDAC6 Inhibitors

The multicomponent synthesis of a mini-library of histone deacetylase inhibitors with imidazo­[1,2-<i>a</i>]­pyridine-based cap groups is presented. The biological evaluation led to the discovery of the hit compound MAIP-032 as a selective HDAC6 inhibitor with promising anticancer activity. The X-ray structure of catalytic domain 2 from Danio rerio HDAC6 complexed with MAIP-032 revealed a monodentate zinc-binding mode

Multicomponent Synthesis and Binding Mode of Imidazo[1,2‑<i>a</i>]pyridine-Capped Selective HDAC6 Inhibitors

The multicomponent synthesis of a mini-library of histone deacetylase inhibitors with imidazo­[1,2-<i>a</i>]­pyridine-based cap groups is presented. The biological evaluation led to the discovery of the hit compound MAIP-032 as a selective HDAC6 inhibitor with promising anticancer activity. The X-ray structure of catalytic domain 2 from Danio rerio HDAC6 complexed with MAIP-032 revealed a monodentate zinc-binding mode

Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines

The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds <b>1g</b>–<b>i</b> showed IC₅₀ values in the low μM and sub-μM range. <b>1g</b>–<b>i</b> revealed low nM IC₅₀ values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of <b>1g</b>–<b>i</b> significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. <b>1g</b>–<b>i</b> interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR

Pro-Apoptotic and Immunostimulatory Tetrahydroxanthone Dimers from the Endophytic Fungus Phomopsis longicolla

Four tetrahydroxanthone dimers (<b>1</b>–<b>4</b>) and four biogenetically related monomers (<b>5</b>–<b>8</b>), including the new derivatives <b>4</b>–<b>6</b>, were isolated from the endophyte Phomopsis longicolla. The absolute configurations of <b>2</b>–<b>4</b> were established for the first time by TDDFT electronic circular dichroism calculations, and that of phomoxanthone A (<b>1</b>) was revised by X-ray crystallography. Phomoxanthone A (<b>1</b>) showed the strongest pro-apoptotic activity when tested against a panel of human cancer cell lines, including cisplatin-resistant cells, whereas it was up to 100-fold less active against healthy blood cells. It was also the most potent activator of murine T lymphocytes, NK cells, and macrophages, suggesting an activation of the immune system in parallel to its pro-apoptotic activity. This dual effect in combating cancer cells could help in fighting resistance during chemotherapy. Preliminary structure–activity studies of isolated compounds and derivatives obtained by semisynthesis (<b>9a</b>–<b>11</b>) hinted at the location of the biaryl axis and the presence of acetyl groups as important structural elements for the biological activity of the studied tetrahydroxanthones