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)

Antiproliferative Homoisoflavonoids and Bufatrienolides from <i>Urginea depressa</i>

Investigation of the South African plant <i>Urginea depressa</i> Baker (Asparagaceae Juss.) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the six new homoisoflavonoids urgineanins A–F (<b>1</b>–<b>6</b>), the two known bufatrienolides <b>7</b> and <b>9</b>, and the new bufatrienolides urginins B and C (<b>8</b> and <b>10</b>). Structures were elucidated based on analysis of their 1D and 2D NMR spectra, electronic circular dichroism, and mass spectrometric data. Five of the six new homoisoflavonoids had good antiproliferative activity against the A2780 ovarian cancer, A2058 melanoma, and H522-T1 human non-small-cell lung cancer cells, and urgineanin A (<b>1</b>) had submicromolar activity against all three cell lines. The four bufatrienolides <b>7</b>–<b>10</b> had strong antiproliferative activity against the same cell line, with IC₅₀ values of 24.1, 11.2, 111, and 40.6 nM, respectively

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

Nitrogen-Containing Dimeric <i>nor</i>-Multiflorane Triterpene from a <i>Turraea</i> sp.

The new triterpene turranoic acid (<b>1</b>) and the new N-containing <i>nor</i>-triterpene turraenine (<b>2</b>), along with triptocallic acid B (<b>3</b>) and esculentoic acid (<b>4</b>) were isolated from leaves of a <i>Turraea</i> sp. Compounds <b>1</b>–<b>3</b> showed weak to moderate in vitro antiplasmodial activity against the chloroquine-resistant <i>Plasmodium falciparum</i> strain FCM29. Compound <b>1</b> also displayed weak cytotoxic activity against the nonsmall lung cancer cell line H522-T1 with an IC₅₀ value of 16.4 μM

Antiproliferative Acetogenins from a <i>Uvaria</i> sp. from the Madagascar Dry Forest

Investigation of the endemic Madagascan plant <i>Uvaria </i>sp<i>.</i> for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new acetogenins. The structures of these two compounds were elucidated on the basis of analysis of their 1D and 2D NMR spectra, circular dichroism, and mass spectrometric data, together with chemical modification. The two acetogenins display weak antiproliferative activity against the A2780 ovarian cancer, the A2058 melanoma, and the H522 lung cancer cell lines

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