Structure Reassignment of Cryptorigidifoliols E and K

The structures of the α-pyrones cryptorigidifoliols E (<b>5</b>) and K (<b>11</b>) have been reassigned as <b>5C</b> and <b>11C</b>

The Quest for a Simple Bioactive Analog of Paclitaxel as a Potential Anticancer Agent

ConspectusPaclitaxel (PTX), introduced into the clinic in 1991, has revealed itself as an effective antimicrotubule drug for treatment of a range of otherwise intractable cancers. Along with docetaxel (DTX) and in combination with other agents such as cisplatin, it has proven to be a first-line therapy. Unfortunately, PTX and DTX carry severe liabilities such as debilitating side effects, rapid onset of resistance, and rather complex molecular structures offering substantial challenges to ease of synthetic manipulation. Consequently, the past 15 years has witnessed many efforts to synthesize and test highly modified analogs based on intuitive structural similarity relationships with the PTX molecular skeleton, as well as efforts to mimic the conformational profile of the ligand observed in the macromolecular tubulin–PTX complex.Highly successful improvements in potency, up to 50-fold increases in IC₅₀, have been achieved by constructing bridges between distal centers in PTX that imitate the conformer of the electron crystallographic binding pose. Much less successful have been numerous attempts to truncate PTX by replacing the baccatin core with simpler moieties to achieve PTX-like potencies and applying a wide range of flexible synthesis-based chemistries. Reported efforts, characterized by a fascinating array of baccatin substitutes, have failed to surpass the bioactivities of PTX in both microtubule disassembly assays and cytotoxicity measurements against a range of cell types. Most of the structures retain the main elements of the PTX C13 side chain, while seeking a smaller rigid bicycle as a baccatin replacement adorned with substituents to mimic the C2 benzoyl moiety and the oxetane ring.We surmise that past studies have been handicapped by solubility and membrane permeability issues, but primarily by the existence of an expansive taxane binding pocket and the discrepancy in molecular size between PTX and the pruned analogs. A number of these molecules offer molecular volumes 50–60% that of PTX, fewer contacts with the tubulin protein, severe mismatches with the PTX pharmacophore, lessened capacity to dispel binding site waters contributing to Δ<i>G</i>_bind, and unanticipated binding poses. The latter is a critical drawback if molecular designs of simpler PTX structures are based on a perceived or known PTX binding conformation. We conclude that design and synthesis of a highly cytotoxic tubulin-assembly agent based on the paclitaxel pharmacophore remains an unsolved challenge, but one that can be overcome by focus on the architecture of the taxane binding site independent of the effective, but not unique, hand-in-glove match represented by the PTX–tubulin complex

Antiplasmodial Diterpenoids and a Benzotropolone from <i>Petradoria pumila</i>

An extract of <i>Petradoria pumila</i> from the Natural Products Discovery Institute was found to have moderate antiplasmodial activity, with an IC₅₀ value between 5 and 10 μg/mL. The four new diterpenoids petradoriolides A–D (<b>1</b>–<b>4</b>), the new benzotropolone petradoriolone (<b>5</b>), and the two known lignans <b>6</b> and <b>7</b> were isolated after bioassay-directed fractionation. The structures and stereochemistries of the new compounds were determined by interpretation of NMR spectroscopy, mass spectrometry, and ECD spectra. Among these compounds, petradoriolide C (<b>3</b>) displayed the most potent antiplasmodial activity, with an IC₅₀ value of 7.3 μM

Antiproliferative Trihydroxyalkylcyclohexenones from <i>Pleiogynium timoriense</i>

Investigation of a DCM extract of the bark of <i>Pleiogynium timoriense</i> from the former Merck collection of natural product extracts for antiproliferative activity indicated that it was active with an IC₅₀ value of 1.3 μg/mL against the A2780 ovarian cancer cell line. Bioassay-directed fractionation of this extract yielded the three new bioactive trihydroxyalkylcyclohexenones <b>1</b>–<b>3</b>. Their structures were determined by a combination of spectroscopic and chemical methods. Compounds <b>1</b>–<b>3</b> exhibited submicromolar antiproliferative activity against the A2780 human ovarian cancer cell line, with IC₅₀ values of 0.8, 0.7, and 0.8 μM, respectively

Synthesis and Antimalarial Activity of Mallatojaponin C and Related Compounds

The phloroglucinol mallotojaponin C (<b>1</b>) from <i>Mallotus oppositifolius</i>, which was previously shown by us to have both antiplasmodial and cytocidal activities against the malaria parasite <i>Plasmodium falciparum</i>, was synthesized in three steps from 2′,4′,6′-trihydroxyacetophenone, and various derivatives were synthesized in an attempt to improve the bioactivity of this class of compounds. Two derivatives, the simple prenylated phloroglucinols <b>12</b> and <b>13</b>, were found to have comparable antiplasmodial activities to that of mallotojaponin C

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

Synthesis and Evaluation of Doxorubicin-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery

Doxorubicin is an effective and widely used cancer chemotherapeutic agent, but its application is greatly compromised by its cumulative dose-dependent side effect of cardiotoxicity. A gold nanoparticle-based drug delivery system has been designed to overcome this limitation. Five novel thiolated doxorubicin analogs were synthesized and their biological activities evaluated. Two of these analogs and PEG stabilizing ligands were then conjugated to gold nanoparticles, and the resulting Au-Dox constructs were evaluated. The results show that release of native drug can be achieved by the action of reducing agents such as glutathione or under acidic conditions, but reductive drug release gave the cleanest drug release. Gold nanoparticles (Au-Dox) were prepared with different loadings of PEG and doxorubicin, and one formulation was evaluated for mammalian stability and toxicity. Plasma levels of doxorubicin in mice treated with Au-Dox were significantly lower than in mice treated with the same amount of doxorubicin, indicating that the construct is stable under physiological conditions. Treatment of mice with Au-Dox gave no histopathologically observable differences from mice treated with saline, while mice treated with an equivalent dose of doxorubicin showed significant histopathologically observable lesions

An Endogenous Bile Acid and Dietary Sucrose from Skin Secretions of Alkaloid-Sequestering Poison Frogs

The skins of Madagascar poison frogs (<i>Mantella</i>) and certain Neotropical poison frogs (<i>Epipedobates</i>, <i>Dendrobates</i>) secrete the new bile acid tauromantellic acid (<b>1</b>), which was found in both wild-caught and captive-born frogs. This is the first molecule of endogenous origin detected in skin secretions from these taxa. Sucrose was also detected in secretions from wild-caught <i>Mantella</i> but not in captive-born frogs, suggesting a dietary origin

Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery

The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented