7 research outputs found
Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents
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 C<sub>31</sub>–C<sub>33</sub> 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 IC<sub>50</sub> 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)Âdesoxypodophyllotoxin
(<b>1</b>) and
4-<i>O</i>-(β-d-glucopyranosyl)Âdehydropodophyllotoxin
(<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 IC<sub>50</sub> 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 IC<sub>50</sub> values of 2.1 ±
0.3 and 4.9 ± 0.1 μM, respectively, while compounds <b>3</b> and <b>6</b> had IC<sub>50</sub> values of >10
μM.
Compound <b>1</b> also had potent antiproliferative activity
against the HCT-116 human colon carcinoma cell line, with an IC<sub>50</sub> 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
IC<sub>50</sub> values of 4.6 and 4.0 μM, respectively