OSDDMalaria:Story so far - Revision history

Matthew Todd: /* Rounds of Synthesis and Evaluation Completed to Date */ added glutathione trapping expt link

Matthew Todd — Sun, 12 May 2013 00:56:39 GMT

Rounds of Synthesis and Evaluation Completed to Date: added glutathione trapping expt link

←Older revision		Revision as of 00:56, 12 May 2013
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	At this point the decision was taken to take the most promising compounds on to advanced biological evaluation, to see what the promise of this class really is (rather than continue to increase potency through analog synthesis). Evaluations to date are as follows.		At this point the decision was taken to take the most promising compounds on to advanced biological evaluation, to see what the promise of this class really is (rather than continue to increase potency through analog synthesis). Evaluations to date are as follows.

-	* '''Metabolic and solubility assays''': The two original GSK compounds (OSM-S-5 and OSM-S-6) and six other compounds made in this project were evaluated by [http://www.pharm.monash.edu.au/staff/sacharman.html Sue Charman's lab at Monash] for their stability in phosphate buffer. The raw data are [http://malaria.ourexperiment.org/biological_data/3101 here] and can be discussed [http://www.thesynapticleap.org/node/401 here]. The GSK originals displayed good solubility but moderate degradation rates. The other compounds were degraded more slowly but at a cost of low solubility. Subsequently the original GSK compound OSM-S-5 was evaluated for stability in human and mouse plasma. The compound was stable in human plasma but susceptible to hydrolysis in mouse plasma. Esterase activity is known to be higher in rodents than in other species which was confirmed using a control compound in this assay (p-nitrophenol acetate) so the results are not too surprising. Lab book page [http://malaria.ourexperiment.org/biological_data/3598/Human_and_Mouse_Plasma_Stability_of_OSMS5PMY_106.html here].	+	* '''Metabolic and solubility assays''': The two original GSK compounds (OSM-S-5 and OSM-S-6) and six other compounds made in this project were evaluated by [http://www.pharm.monash.edu.au/staff/sacharman.html Sue Charman's lab at Monash] for their stability in phosphate buffer. The raw data are [http://malaria.ourexperiment.org/biological_data/3101 here] and can be discussed [http://www.thesynapticleap.org/node/401 here]. The GSK originals displayed good solubility but moderate degradation rates. The other compounds were degraded more slowly but at a cost of low solubility. Subsequently the original GSK compound OSM-S-5 was evaluated for stability in human and mouse plasma. The compound was stable in human plasma but susceptible to hydrolysis in mouse plasma. Esterase activity is known to be higher in rodents than in other species which was confirmed using a control compound in this assay (p-nitrophenol acetate) so the results are not too surprising. Lab book page [http://malaria.ourexperiment.org/biological_data/3598/Human_and_Mouse_Plasma_Stability_of_OSMS5PMY_106.html here]. A [http://malaria.ourexperiment.org/biological_data/6729/Glutathione_Trapping_Study_for_OSMS35_.html glutathione trapping experiment] was carried out on OSM-S-35 as representative of the Near Neighbour series, giving some identification of possible trapped metabolites, but the levels observed were not large.
	* '''hERG''': One of the original GSK compounds (OSM-S-5) plus one of the most potent novel compounds identified to date (OSM-S-35) were subjected to the [http://malaria.ourexperiment.org/biological_data/2999 hERG assay and passed], perhaps implying that this class of compounds should not exhibit undesirable cardiac side effects. Discussion page [http://www.thesynapticleap.org/node/402 here].		* '''hERG''': One of the original GSK compounds (OSM-S-5) plus one of the most potent novel compounds identified to date (OSM-S-35) were subjected to the [http://malaria.ourexperiment.org/biological_data/2999 hERG assay and passed], perhaps implying that this class of compounds should not exhibit undesirable cardiac side effects. Discussion page [http://www.thesynapticleap.org/node/402 here].
	* '''Late Stage Gametocyte Assay''': Four of the compounds have also been [http://malaria.ourexperiment.org/biological_data/3066 evaluated in a late stage gametocyte assay] with very interesting results indicating unusually high activity in blocking the transmission of the parasite. The original GSK compound OSM-S-5 was inactive. Discussion page [http://www.thesynapticleap.org/node/403 here].		* '''Late Stage Gametocyte Assay''': Four of the compounds have also been [http://malaria.ourexperiment.org/biological_data/3066 evaluated in a late stage gametocyte assay] with very interesting results indicating unusually high activity in blocking the transmission of the parasite. The original GSK compound OSM-S-5 was inactive. Discussion page [http://www.thesynapticleap.org/node/403 here].

Alice E Williamson: Feb update prior to meeting,

Alice E Williamson — Tue, 26 Feb 2013 01:00:20 GMT

Feb update prior to meeting,

←Older revision		Revision as of 01:00, 26 February 2013
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	[[Image:tssfar.png\|thumb\|center\|700px\| '''Representative Examples from the Third Round]]		[[Image:tssfar.png\|thumb\|center\|700px\| '''Representative Examples from the Third Round]]

-	~~Currently (Dec~~ 2012) there ~~remain~~ a [http://www.thesynapticleap.org/node/429 few compounds] which ~~need~~ synthetic input from any labs interested in contributing. The project has to date had no luck in securing donations of the compounds from commercial suppliers. On considering some structurally 'similar' active compounds from the TCAMS set, the team have also decided to synthesise a few [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/LzxZxukacpn extra compounds] plus hybrids, in order to assess their biological activity~~. An open consultation is set to take place on Monday 17th December in order to decide next steps~~.	+	At the end of 2012, there remained a [http://www.thesynapticleap.org/node/429 few compounds] which needed synthetic input from any labs interested in contributing. Patrick Thompson, a collaborator from the University of Edinburgh built on Matin Dean's work on the [http://malaria.ourexperiment.org/tcmdc_ap/month/1356998400 sulfonamide] whilst Murray Robertson and Alice Williamson focused on synthesising further analogues of the [http://malaria.ourexperiment.org/near_neighbours near-neighbours], in order to find potent molecules with increased solubility. The near-neighbours were [https://plus.google.com/u/0/b/114702323662314783325/114702323662314783325/posts/W5Sdz8J3iur evaluated] and a number of potent compounds were discovered, some with lower LogP than the first set of near-neighbour compounds. An open consultation is set to take place on Tuesday 26th February in order to discuss the latest biology results and to decide the next steps for the project.
		+
		+	The project has to date had no luck in securing donations of the compounds from commercial suppliers. On considering some structurally 'similar' active compounds from the TCAMS set, the team have also decided to synthesise a few [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/LzxZxukacpn extra compounds] plus hybrids, in order to assess their biological activity.

	==What Are the Compounds Doing?==		==What Are the Compounds Doing?==

Jim Cronshaw: updated summary

Jim Cronshaw — Sat, 19 Jan 2013 11:15:23 GMT

updated summary

←Older revision		Revision as of 11:15, 19 January 2013
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	==Related Series==		==Related Series==

-	The arypyrrole series was the first to be examined. Two other interesting-looking starting points from the GSK set, based on a [http://openwetware.org/wiki/OSDDMalaria:GSK_Triazolourea_Singleton triazolourea] and a [http://openwetware.org/wiki/OSDDMalaria:GSK_Amino-thienopyrimidine_Series thienopyrimidine], were the focus of [http://openwetware.org/wiki/User:Jim_Cronshaw James Cronshaw's] honours [http://figshare.com/articles/ThesisforUpload.pdf/102049 thesis] at Sydney University. The triazolourea (OSM-S-56) was found to be [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/QfynoBafbXt even more active] than the original GSK hit (TCMDS 134395). James ~~is in the process of synthesising~~ the [http://malaria.ourexperiment.org/aminotpseries/5827/Suzuki_coupling_using_the_same_conditions_that_are_used_to_generate_boronate_esters.html thienopyrimidine] ~~to confirm activity~~, ~~upon which time~~ it will be necessary to decide which, if either, are to be taken on further. In general a strategy for the project is to decide as early as possible which series are looking attractive biologically, because there are still a lot of leads to pursue. If any of these structures look synthetically attractive to you based on your previous experience, please consider joining the project. Some of these molecules are quite straightforward to make and would be suitable for undergraduate lab classes.	+	The arypyrrole series was the first to be examined. Two other interesting-looking starting points from the GSK set, based on a [http://openwetware.org/wiki/OSDDMalaria:GSK_Triazolourea_Singleton triazolourea] and a [http://openwetware.org/wiki/OSDDMalaria:GSK_Amino-thienopyrimidine_Series thienopyrimidine], were the focus of [http://openwetware.org/wiki/User:Jim_Cronshaw James Cronshaw's] honours [http://figshare.com/articles/ThesisforUpload.pdf/102049 thesis] at Sydney University. The triazolourea (OSM-S-56) was found to be [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/QfynoBafbXt even more active] than the original GSK hit (TCMDS 134395). James has synthesised the [http://malaria.ourexperiment.org/aminotpseries/5827/Suzuki_coupling_using_the_same_conditions_that_are_used_to_generate_boronate_esters.html thienopyrimidine] series lead, and we are awaiting confirmation of the compounds antimalarial activity. If the lead compound is confirmed as active then it will be necessary to decide which, if either, of the series are to be taken on further. In general a strategy for the project is to decide as early as possible which series are looking attractive biologically, because there are still a lot of leads to pursue. If any of these structures look synthetically attractive to you based on your previous experience, please consider joining the project. Some of these molecules are quite straightforward to make and would be suitable for undergraduate lab classes.

	==Comments==		==Comments==

Jim Cronshaw: cleaned up broken links

Jim Cronshaw — Sat, 19 Jan 2013 11:13:39 GMT

cleaned up broken links

←Older revision		Revision as of 11:13, 19 January 2013
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	==Related Series==		==Related Series==

-	The arypyrrole series was the first to be examined. Two other interesting-looking starting points from the GSK set, based on a [http://openwetware.org/wiki/OSDDMalaria:GSK_Triazolourea_Singleton triazolourea] and a [http://openwetware.org/wiki/OSDDMalaria:GSK_Amino-thienopyrimidine_Series thienopyrimidine], were the focus of [~~https~~://~~plus~~.~~google.com~~/u/~~0/b/114702323662314783325/115975655197247500095/posts~~ James Cronshaw's] ~~honour's~~ [~~https~~://~~plus.google~~.com/b/~~114702323662314783325/115975655197247500095/posts~~/~~8KTWdY7P4ZF~~ thesis] at Sydney University. The triazolourea (OSM-S-56) was found to be [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/QfynoBafbXt even more active] than the original GSK hit (TCMDS 134395). James is in the process of synthesising the [http://malaria.ourexperiment.org/aminotpseries/5827/Suzuki_coupling_using_the_same_conditions_that_are_used_to_generate_boronate_esters.html thienopyrimidine] to confirm activity, upon which time it will be necessary to decide which, if either, are to be taken on further. In general a strategy for the project is to decide as early as possible which series are looking attractive biologically, because there are still a lot of leads to pursue. If any of these structures look synthetically attractive to you based on your previous experience, please consider joining the project. Some of these molecules are quite straightforward to make and would be suitable for undergraduate lab classes.	+	The arypyrrole series was the first to be examined. Two other interesting-looking starting points from the GSK set, based on a [http://openwetware.org/wiki/OSDDMalaria:GSK_Triazolourea_Singleton triazolourea] and a [http://openwetware.org/wiki/OSDDMalaria:GSK_Amino-thienopyrimidine_Series thienopyrimidine], were the focus of [http://openwetware.org/wiki/User:Jim_Cronshaw James Cronshaw's] honours [http://figshare.com/articles/ThesisforUpload.pdf/102049 thesis] at Sydney University. The triazolourea (OSM-S-56) was found to be [https://plus.google.com/b/114702323662314783325/114702323662314783325/posts/QfynoBafbXt even more active] than the original GSK hit (TCMDS 134395). James is in the process of synthesising the [http://malaria.ourexperiment.org/aminotpseries/5827/Suzuki_coupling_using_the_same_conditions_that_are_used_to_generate_boronate_esters.html thienopyrimidine] to confirm activity, upon which time it will be necessary to decide which, if either, are to be taken on further. In general a strategy for the project is to decide as early as possible which series are looking attractive biologically, because there are still a lot of leads to pursue. If any of these structures look synthetically attractive to you based on your previous experience, please consider joining the project. Some of these molecules are quite straightforward to make and would be suitable for undergraduate lab classes.

	==Comments==		==Comments==

Alice E Williamson: /* Rounds of Synthesis and Evaluation Completed to Date */

Alice E Williamson — Mon, 17 Dec 2012 02:00:03 GMT