Showing papers by "Philip L. Fuchs published in 2009"
TL;DR: A comprehensive program for the synthesis of natural (or unnatural) products is analogous to the construction of a pyramid, where careful planning followed by installation of numerous levels of support are required to complete the edifice.
Abstract: A comprehensive program for the synthesis of natural (or unnatural) products is analogous to the construction of a pyramid. Careful planning followed by installation of numerous levels of support are required to complete the edifice. Specific “cornerstone” strategies are typically major motivations for undertaking the program. Finally, the venture reflects the desire of the research team to construct a lasting monument to their creativity and hard work (Figure 1). * Corresponding author. E-mail: pfuchs@purdue.edu. Chem. Rev. 2009, 109, 2315–2349 2315
285 citations
TL;DR: This account will focus on the advances in the syntheses of cephalostatins and ritterazines over the past 15 years emphasizing the different strategies adopted, key transformations, and methods for achieving the late construction of the dissymmetric bissteroidal pyrazine framework.
Abstract: The search for natural products of medicinal significance led the Pettit group to isolate the cephalostatins1 (from the hemichordate worm Cephalodiscus gilchristi,2 e.g. cephalostatin 1 (1), and the Fusetani team to the ritterazines3 (from the tunicate Ritterella tokioka, e.g. ritterazine B (2)), respectively. The cephalostatins and ritterazines, are a family of 45 trisdecacyclic bissteroidal pyrazines that display striking cytotoxicity against human tumors (~1 nM in the 2-day NCI 60 cell panel;4 and in some cases ~10 fM 6-day in the Purdue mini panel5), thereby ranking them among the most potent anticancer agents tested by the NCI.
Computer matching at the NCI using the COMPARE program have revealed several additional compounds exhibiting similar profiles to the Cephalostatin/Ritterazine family. These compounds include OSW-16 (3) a monosteroidal saponin glycoside from the garden perennial Ornithogalum saundersiae (GI50 of 0.8 nM in the NCI 60 cancer cell line), and solamargine7 (4) (from Solanum species) as additional possible candidates for cancer therapy. OSW-1 (3) shows low toxicity to normal human pulmonary cells but encouraging activity against malignant solid tumor cells. Solamargine (4), is an active ingredient of creme Curaderm®, claimed to be 100% effective against melanomas in preliminary clinical trials without significant side effects or recurrence of cancer 10 years after treatment (Figure 1).8
Open in a separate window
Figure 1
Steroidal anticancer agents.
88 citations
TL;DR: The C14,15-dihydro-C22,25-epi north unit of cephalostatin 1 has been synthesized in 11 operations from commercially available hecogenin acetate via multiple reductions and oxidations using a base-triggered cyclization cascade.
22 citations
TL;DR: To apply the collection of enantiopure 7-ring vinyl sulfones to probe the anticancer SAR of a series of computer-designed (+)-discodermolide analogs, the ozonolytic reactivity of transposed cyclic vinyl phosphonates was explored.
13 citations
TL;DR: Methods have been developed for regio- and stereoselective 1, 4-syn or 1,4-anti methylation of seven-membered epoxyvinylsulfones and the methods described were assayed on four diastereomeric stereodiads and on their parent epoxide.
Abstract: Methods have been developed for regio- and stereoselective 1,4-syn or 1,4-anti methylation of seven-membered epoxyvinylsulfones. 1,4-Syn addition is achieved via the combination of Me(2)Zn and catalytic Li(2)CuCl(4), a hitherto unexplored reagent combination. The complementary 1,4-anti addition relies on Cu(I) catalyzed methyl Grignard addition or (CH(3))(3)Al assisted CH(3)Cu addition. The methods described were assayed on four diastereomeric stereodiads and on their parent epoxide.
8 citations
TL;DR: The Cephalostatins and ritterazines as discussed by the authors are a family of 45 bissteroidal pyrazines that display striking cytotoxicity against human tumors and are among the most potent anticancer agents tested by the NCI.
Abstract: The search for natural products of medicinal significance led the Pettit group to isolate the cephalostatins1 (from the hemichordate worm Cephalodiscus gilchristi,2 e.g. cephalostatin 1 (1), and the Fusetani team to the ritterazines3 (from the tunicate Ritterella tokioka, e.g. ritterazine B (2)), respectively. The cephalostatins and ritterazines, are a family of 45 trisdecacyclic bissteroidal pyrazines that display striking cytotoxicity against human tumors (~1 nM in the 2-day NCI 60 cell panel;4 and in some cases ~10 fM 6-day in the Purdue mini panel5), thereby ranking them among the most potent anticancer agents tested by the NCI.
Computer matching at the NCI using the COMPARE program have revealed several additional compounds exhibiting similar profiles to the Cephalostatin/Ritterazine family. These compounds include OSW-16 (3) a monosteroidal saponin glycoside from the garden perennial Ornithogalum saundersiae (GI50 of 0.8 nM in the NCI 60 cancer cell line), and solamargine7 (4) (from Solanum species) as additional possible candidates for cancer therapy. OSW-1 (3) shows low toxicity to normal human pulmonary cells but encouraging activity against malignant solid tumor cells. Solamargine (4), is an active ingredient of creme Curaderm®, claimed to be 100% effective against melanomas in preliminary clinical trials without significant side effects or recurrence of cancer 10 years after treatment (Figure 1).8
Open in a separate window
Figure 1
Steroidal anticancer agents.