Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents

The design, synthesis, and biological evaluation of irciniastatin A (<b>1</b>) analogues, achieved by removal of three synthetically challenging structural units, as well as by functional group manipulation of the C(11) substituent of both irciniastatins A and B (<b>1</b> and <b>2</b>), has been achieved. To this end, we first designed a convergent synthetic route toward the diminutive analogue (+)-<i>C</i>(8)-desmethoxy-<i>C</i>(11)-deoxy-<i>C</i>(12)-didesmethylirciniastatin (<b>6</b>). Key transformations include an acid-catalyzed 6-<i>exo</i>-tet pyran cyclization, a chiral Lewis acid mediated aldol reaction, and a facile amide union. The absolute configuration of <b>6</b> was confirmed via spectroscopic analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure–activity relationship (SAR) studies of <b>6</b> demonstrate that the absence of the three native structural units permits access to analogues possessing cytotoxic activity in the nanomolar range. Second, manipulation of the C(11) position, employing late-stage synthetic intermediates from our irciniastatin syntheses, provides an additional five analogues (<b>7</b>–<b>11</b>). Biological evaluation of these analogues indicates a high functional group tolerance at position C(11)

Structures and Cytotoxic Evaluation of New and Known Acyclic Ene-Ynes from an American Samoa <i>Petrosia</i> sp. Sponge

Four new compounds, (−)-petrosynoic acids A–D (<b>1</b>–<b>4</b>), and five known congeners, pellynols A (<b>5</b>), C (<b>6</b>), D (<b>7</b>), F (<b>8</b>), and I (<b>9</b>), were isolated from a <i>Petrosia</i> sp. marine sponge collected in American Samoa. Isolation work was guided by cytotoxicity against human lung cancer cells (H460). The structures of the C₃₁–C₃₃ polyacetylenes (<b>1</b>–<b>9</b>) were determined on the basis of 1D- and 2D-NMR analysis, mass spectrometry, and comparison of specific rotation values. Compounds <b>1</b>–<b>9</b> were found to be broadly cytotoxic with limited selectivity for cancer cells, as they were all moderately active against the A2058 (melanoma), H522-T1 (lung), and H460 (lung) human cancer cell lines as well as IMR-90 quiescent human fibroblast cells

Mycoleptodiscins A and B, Cytotoxic Alkaloids from the Endophytic Fungus <i>Mycoleptodiscus</i> sp. F0194

Two novel reddish-orange alkaloids, mycoleptodiscin A (<b>1</b>) and mycoleptodiscin B (<b>2</b>), were isolated from liquid cultures of the endophytic fungus <i>Mycoleptodiscus</i> sp. that had been isolated from <i>Desmotes incomparabilis</i> in Panama. Elucidation of their structures was accomplished using 1D and 2D NMR spectroscopy in combination with IR spectroscopic and MS data. These compounds are indole-terpenes with a new skeleton uncommon in nature. Mycoleptodiscin B (<b>2</b>) was active in inhibiting the growth of cancer cell lines with IC₅₀ values in the range 0.60–0.78 μM

Antiproliferative Compounds from <i>Cleistanthus boivinianus</i> from the Madagascar Dry Forest

The two new lignans 3α-<i>O</i>-(β-d-glucopyranosyl)­desoxypodophyllotoxin (<b>1</b>) and 4-<i>O</i>-(β-d-glucopyranosyl)­dehydropodophyllotoxin (<b>2</b>) were isolated from <i>Cleistanthus boivinianus</i>, together with the known lignans deoxypicropodophyllotoxin (<b>3</b>), (±)-β-apopicropodophyllin (<b>4</b>), (−)-desoxypodophyllotoxin (<b>5</b>), (−)-yatein (<b>6</b>), and β-peltatin-5-<i>O</i>-β-d-glucopyranoside (<b>7</b>). The structures of all compounds were characterized by spectroscopic techniques. Compounds <b>1</b>, <b>4</b>, and <b>5</b> showed potent antiproliferative activities against the A2780 ovarian cancer cell line, with IC₅₀ values of 33.0 ± 3.6, 63.1 ± 6.7, and 230 ± 1 nM, respectively. Compounds <b>2</b> and <b>7</b> showed only modest A2780 activities, with IC₅₀ values of 2.1 ± 0.3 and 4.9 ± 0.1 μM, respectively, while compounds <b>3</b> and <b>6</b> had IC₅₀ values of >10 μM. Compound <b>1</b> also had potent antiproliferative activity against the HCT-116 human colon carcinoma cell line, with an IC₅₀ value of 20.5 nM, and compound <b>4</b> exhibited modest antiproliferative activity against the A2058 human caucasian metastatic melanoma and MES-SA human uterine sarcoma cell lines, with IC₅₀ values of 4.6 and 4.0 μM, respectively