Design and synthesis of cosalane, a novel anti-HIV …
Synthesis of a cosalane analog with an extended ..
Design and synthesis of cosalane, a novel anti-HIV agent.
In an attempt to target the ileal bile acid transporter and thus facilitate oral bioavailability, a cosalane analog was synthesized in which the disalicylmethane pharmacophore is attached to a bile acid through a linker chain appended to C-17 of the steroid nucleus.
For the synthesis of 9e (), methyl lithocholate (10e) was converted to the thiocarmabate 11e (TCDI, DMAP; ) followed by a modified Barton-McCombie deoxygenation., The deoxygenation was sensitive to the reaction conditions; formation of a by-product arising from the reduction of the thiocarbamate moiety was observed under the standard Barton-McCombie protocol. This could be overcome by the slow addition (i.e., over 1 h) of the substrate and azobisisobutyronitrile (AIBN) to a dilute solution of an excess of tri-nbutyltin hydride (0.06 M, 4.0 equiv) at toluene reflux.
PubMed - National Center for Biotechnology Information
The structural influence on olfactory activity in these nonnatural 5β-steroidal sulfates was further examined as a function of oxygenation at the C3-, C7-, and C12-positions of the steroid skeleton. Interestingly, the C7-hydroxy substituent appears to be more important to olfactory activity than that of the C12-substituent (cf. 9b vs. 9c, ). Previous results have shown that the C24-O-sulfate is also critical. It appears that the PS (1) binding pocket is discerning a large portion, but not the entirety, of each of these structures. Because allo-configured steroids are more difficult and expensive to synthesize than their 5β-counterparts, this information should be useful in the further development of pheromone analogs (e.g., 5 β PADS) for use in controlling the sea lamprey, which is invasive in the Great lakes of North America
This study has resulted in the synthesis of several new bile acid derivatives. These were used to demonstrate that sea lamprey olfactory receptors for PS (1) are relatively insensitive to the allo-configuration at C5 but that structural features elsewhere in the molecules are discerned. 5β-Petromyzonol sulfate (9a) elicits EOG responses that are only slightly smaller than those of natural (allo) PS (1). Further, mixture studies demonstrated that 9a and 1 interact with the same receptor (ICI = ca. 1). This result is analogous to previous findings for allocholic (7) vs. cholic (10a) acid. In the only other example of a steroidal odorant where binding properties have been explored in detail–the goldfish sex pheromone 17,20β-dihydroxy-4-pregenen-3-one–single changes in the structural features decreased binding affinity by 1–2 orders of magnitude. The present work also sheds some insight on possible differences between olfactory receptors for modern teleost (bony) fish and lampreys. In particular, single unit recording from the catfish olfactory bulb suggests that this teleost’s olfactory receptors are more sensitive to hydroxylation at the C7 and C12 positions than those of the sea lamprey. In other ways both groups of fishes are similar. They both exhibit specific and remarkable sensitivities for steroids with allo-configurations as well as taurine, glycine, and sulfated conjugates, although the details of these relationships have yet to be fully explored.
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The study reported here had two related objectives; to synthesize a series of 5β-bile acids and to determine both the sensitivity and specificity with which they are discerned by the sea lamprey olfactory system. Toward that end, we prepared the analogs 9a [the 5β-epimer of PS (1)], 9b–e (less highly oxygenated analogs of 9a), and 9f (the C3-keto analog of 9a) () and then tested their olfactory activity using electro-olfactogam recording (EOG).
The olfactory activity of synthesized steroids was assayed using electro-olfactogram (EOG) recording, which is an extracellular, multiunit electrophysiological recording method that measures summated generator potentials from olfactory receptors. This technique had previously been successfully employed to describe the olfactory potency and structure-activity relationships of steroidal odorants in the sea lamprey.,, Three types of experiments were performed in a sequential fashion to first identify structures that had significant olfactory activity and then to determine whether and how they bound to the olfactory receptor(s) that recognize native allo-compounds. The last step involved two types of mixture experiments that used both natural (allo-) and nonnatural (5 β–) compounds to test whether and how different steroids bound with similar receptors.
Synthesis and anti-HIV activity of a bile acid ..
RAFT Agent Design and Synthesis - [PDF Document]
RAFT Agent Design and Synthesis Daniel J
Keddie, Graeme Moad,* Ezio Rizzardo, ..
rate of dna synthesis in eukaryotes; ..
Synthesis, metabolism and cellular permeability of enzymatically stable dipeptide prodrugs of acyclovir
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A variety of unnatural bile acid derivatives (9a–9f) were synthesized and used to examine the specificity with which the sea lamprey (Petromyzon marinus) olfactory system detects these compounds. These compounds are analogs of petromyzonol sulfate (PS, 1), a component of the sea lamprey migratory pheromone. Both the stereochemical configuration at C5 (i.e., 5α vs. 5β) and the extent and sites of oxygenation (hydroxylation or ketonization) of the bile acid derived steroid skeleton were evaluated by screening the compounds for olfactory activity using electro-olfactogram recording. 5β-Petromyzonol sulfate (9a) elicited a considerable olfactory response at sub-nanomolar concentration. In addition, less oxygenated systems (i.e., 9b–9e) elicited olfactory responses, albeit with less potency. The sea lamprey sex pheromone mimic 9f (5β-3-ketopetromyzonol sulfate) was also examined and found to produce a much lower olfactory response. Mixture studies conducted with 9a and PS (1) suggest that stimulation is occurring via similar modes of activation, demonstrating a relative lack of specificity for recognition of the allo-configuration (i.e., 5α) in sea lamprey olfaction. This attribute could facilitate design of pheromone analogs to control this invasive species.
Exploitation of Bile Acid Transport Systems in Prodrug Design
Because allo steroids are rare amongst mammals, relatively few have been synthesized. The sea lamprey and related lampreys produce the biologically active allo steroids, allocholic acid (7, ), PS (1), and PADS (2). Only for the first of these steroids has the analogous 5β-isomer, namely cholic acid (10a, ), been tested for olfactory activity in lamprey and other fish. Otherwise, the importance of the more rare allo-configuration to the underlying structure-activity relationship (SAR) has not been studied. Similarly, the carps and other cyprinids, the second largest family of fishes within over 1000 species, produce and detect cyprinol sulfate (8, )., Other fishes detect 8 with high sensitivity. However, neither the behavioral function nor the importance of the allo-configuration in olfactory detection have been explicitly tested. Indeed, the overall importance to the fish olfactory system of most structural features associated with this class of (several hundred Dalton) sulfated allo steroids has not been systematically explored. This is notable because bile acids include the largest olfactory ligands described for a fish (PADS is the largest), so it is reasonable to ask whether the entire structure is discerned.
a cholic acid analog of cosalane ..
The synthesis of 5β-petromyzonol sulfate (9a) was achieved by protection of cholic acid (10a) as the triformate ester 11a (formic acid, 55 °C) and subsequent chemoselective reduction of the carboxylic acid with borane–dimethylsulfide complex to provide the primary alcohol 12a (). Sulfation of 12a was effected by a modified procedure in which a suspension of sulfur trioxide–pyridine complex in methylene chloride was solubilized by the addition of triethylamine (4 equiv); this permits sulfation to occur at ambient temperature rather than the higher temperatures typically required for sulfation using sulfur–trioxide in pyridine. The triformate 13a was saponified (aq NaOH, MeOH) with concomitant triethylammonium–sodium exchange to provide 9a. The analogous compounds 9b and 9c, derived from deoxycholic acid (10b) and chenodeoxycholic acid (10c) respectively, were synthesized using a very similar protocol.
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