“…The acid was coupled to alkenol 13 5d using 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), and the resulting olefin was oxidized to acid 16 . After the acid was coupled to alcohol 17 ,5d the Cbz carbamate and benzyl ester were selectively deprotected in the presence of the PMB ether by hydrogenation over W-2 Raney nickel provided 19 in a good yield of 58% over the two steps. 1 …”
Section: Resultsmentioning
confidence: 99%
“…With the aid of 1 H, 1 H-NOESY data, computation revealed that the major s - cis rotamer of hapalosin and the single s - trans rotamer of the non- N -Me hapalosin analog (having a secondary N−H amide bond instead of the tertiary N−Me amide bond in hapalosin) have very different conformations. By contrast, the minor s - trans rotamer of hapalosin and the non- N -Me analog have very similar conformations 5d. The non- N -Me analog was found to possess substantially weaker MDR-reversing property than hapalosin. 5f, …”
Section: Introductionmentioning
confidence: 99%
“…By contrast, the minor s - trans rotamer of hapalosin and the non- N -Me analog have very similar conformations 5d. The non- N -Me analog was found to possess substantially weaker MDR-reversing property than hapalosin. 5f, …”
Four analogs were synthesized which have
trans-4-hydroxyl-l−proline replacing the
N-Me-l-phenylalanine moiety in hapalosin. The triamide analog of hapalosin
containing two secondary
amide bonds in lieu of the two ester bonds in hapalosin was also
synthesized. Conformations of
hapalosin, the triamide analog, and two of the four proline analogs in
chloroform were calculated
utilizing distance constraints between NOESY-correlated protons.
The lowest-energy, distance-constrained conformation of hapalosin is similar to that of the triamide
analog and does not differ
substantially from that of the two proline analogs. All
conformations have an s-cis tertiary
amide
bond. The analogs' ability to reverse
P-glycoprotein-mediated multidrug resistance was
evaluated
in cytotoxicity and drug accumulation assays using MCF-7/ADR cells
which overexpress P-glycoprotein. Two of the proline analogs are more potent than
hapalosin (which has a similar
activity as verapamil) whereas the other two proline analogs and the
triamide analog are less active
than hapalosin.
“…The acid was coupled to alkenol 13 5d using 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), and the resulting olefin was oxidized to acid 16 . After the acid was coupled to alcohol 17 ,5d the Cbz carbamate and benzyl ester were selectively deprotected in the presence of the PMB ether by hydrogenation over W-2 Raney nickel provided 19 in a good yield of 58% over the two steps. 1 …”
Section: Resultsmentioning
confidence: 99%
“…With the aid of 1 H, 1 H-NOESY data, computation revealed that the major s - cis rotamer of hapalosin and the single s - trans rotamer of the non- N -Me hapalosin analog (having a secondary N−H amide bond instead of the tertiary N−Me amide bond in hapalosin) have very different conformations. By contrast, the minor s - trans rotamer of hapalosin and the non- N -Me analog have very similar conformations 5d. The non- N -Me analog was found to possess substantially weaker MDR-reversing property than hapalosin. 5f, …”
Section: Introductionmentioning
confidence: 99%
“…By contrast, the minor s - trans rotamer of hapalosin and the non- N -Me analog have very similar conformations 5d. The non- N -Me analog was found to possess substantially weaker MDR-reversing property than hapalosin. 5f, …”
Four analogs were synthesized which have
trans-4-hydroxyl-l−proline replacing the
N-Me-l-phenylalanine moiety in hapalosin. The triamide analog of hapalosin
containing two secondary
amide bonds in lieu of the two ester bonds in hapalosin was also
synthesized. Conformations of
hapalosin, the triamide analog, and two of the four proline analogs in
chloroform were calculated
utilizing distance constraints between NOESY-correlated protons.
The lowest-energy, distance-constrained conformation of hapalosin is similar to that of the triamide
analog and does not differ
substantially from that of the two proline analogs. All
conformations have an s-cis tertiary
amide
bond. The analogs' ability to reverse
P-glycoprotein-mediated multidrug resistance was
evaluated
in cytotoxicity and drug accumulation assays using MCF-7/ADR cells
which overexpress P-glycoprotein. Two of the proline analogs are more potent than
hapalosin (which has a similar
activity as verapamil) whereas the other two proline analogs and the
triamide analog are less active
than hapalosin.
“…Hapalosin has also attracted the attention of synthetic chemists. Armstrong reported the first total synthesis in 1995 (Scheme ). The synthesis was achieved by coupling of the amine 99 with the acid chloride 98 to afford amide 100 .…”
Section: The Role Of Diverted Total Synthesis In Drug Discoverymentioning
Natural products commonly produced as secondary metabolites of various plants and micro-organisms represent a diverse chemical space of compounds. The diversity of natural products makes them an attractive target for interrogation by both chemists and biologists alike. Indeed, the study of 12-membered macrolactones has already led to the discovery of lead drug compounds and new biological targets, which has motivated the development of diverted total synthetic routes to libraries of analogs. This review explores the discovery, biological characterization, and synthesis of several 12-membered macrolactones, exploiting examples that underscore their importance in the drug discovery field. It is our hope that this review will motivate further interest in this class of natural products, a group of molecules that we think merit the classification of 'privileged scaffolds' within the medicinal chemistry community, to further investigate and develop novel compounds with promising bioactivity.
K E Y W O R D Santibiotic, biosynthesis, diverted total synthesis, macrolactone, natural product
“…Hapalosin, a small cyclic depsipeptide isolated from Hapalosiphon welwitschii, inhibits multidrug resistance mediated by P-glycoprotein (Stratmann et al 1994;Dinh and Armstrong 1995). Kalkitoxin, a potent sodium-channel blocker (Wu et al 2000;LePage et al 2005), and antillatoxin, a potent activator of sodium channels (Orjala et al 1995;Nogle 2001;Cao 2010), are both lipopeptides isolated from Lyngbya majuscula.…”
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