887:
878:(ETC) complex 1. It remains unknown how exactly kalkitoxin binds to the voltage-gated sodium channel. Neurotoxin sit 1 and 2 have been ruled out as possible binding sites, whereas neurotoxin site 7 is suggested as binding site for kalkitoxin. This is probable, because there is inhibition of the channel by kalkitoxin when deltamethrin, which has positive allosteric effects, is present. This could be because molecular determinants for binding are similar in kalkitoxin and deltamethrin.
1019:. Therefore, kalkitoxin's HIF-1 inhibitory ability positions it as a potentially promising molecule to counteract the progression of some solid tumor cancers by blocking the tumor proliferative response to hypoxia. The caveat to kalkitoxin's promising anti-proliferative properties is its neurotoxic effects. At concentrations comparable to those required for tumor-selective cytotoxicity, kalkitoxin induces cell death when applied to rat
1881:
641:
stereochemistry exhibited in natural (+)-kalkitoxin decreases moving towards the chiral centers in the core of the molecule, while the more terminal chiral centers and amide methyl group are increasingly crucial for toxicity. In a study which assayed for the toxicity of kalkitoxin and various analogs against brine shrimp, the analogs which experienced the least significant loss of potency were
24:
843:
at each addition by selecting the chirality of each benzoate ester added. Furthermore, this avoids repetitive interconversion and purification steps normally required for repeat chain extensions, which increases yield and efficiency and decreases labor. This synthesis capitalized on this technique by
590:
protons. This allows for the determination of relative stereochemistry of C8 and C10 to the C9 protons through ] values, so as to relate the relative stereochemistry of C8 to C10. These methods yielded a relative stereochemistry of 7R, 8S, 10S for the aliphatic chain stereocenters. Stereochemistry at
585:
of the atoms being analyzed, allowing for the determination of chirality. This was used to determine the stereochemistry of chiral centers at C7, C8, and C10. Because C7 and C8 are adjacent stereocenters, these techniques allowed for immediate determination of their relative stereochemistry, however
650:
of C7, supporting the trend of decreased SAR correlation at core chiral centers on the aliphatic chain. Epimerization at C3, the attachment point of the terminal alkene to the thiazoline ring, further decreases potency of kalkitoxin, in agreement with the thiazoline ring and overall conformation of
645:
at either C8 or C10. This indicates that C8 and C10 chiralities in natural (+)-kalkitoxin are the least critical for toxic biological activity. It is apparent that C10 chirality is less critical than C8, because the epimer of (+)-kalkitoxin at C10 is more potent than the epimer at C8. Furthermore,
983:
used an in-vitro assay to test solid tumor selectivity of kalkitoxin's previously demonstrated cytotoxicity against the human colon cell line HCT-116. The assay measured the extent of differential cytotoxicity of kalkitoxin and various analogous structures by observing differential cytotoxicity
607:
derivative was L-cysteic acid, indicating R absolute stereochemistry at C3. The absolute stereochemistry of the total molecule was determined by synthesizing the possible configurations of the already determined relative chiralities, and comparison of these to natural
Kalkitoxin via C NMR
640:
ring for its action. Kalkitoxin analogs lacking the complete thiazoline ring exhibit on the order of 1000-fold decreased toxicity to solid tumor cell lines. This indicates the thiazoline ring structure is a crucial component of kalkitoxin's mechanism of cytotoxicity. The necessity of the
831:
chain extensions, such as the one found in kalkitoxin. This novel approach is achieved through the use of reagent-controlled chain extension of a boronic ester, which relies on a spontaneous 1,2-migration after formation of an intermediate compound incorporating a newly added lithiated
928:-1 (HIF-1) activation. HIF-1 is a transcription factor, which enhances the expression of genes that increase oxygen availability, as well as genes that decrease oxygen consumption. Inhibition of HIF-1, which is one of the main effects of kalkitoxin, thus induces cellular hypoxia.
778:
Another point of diversion between these two syntheses is the number of carbons separating the keto-auxiliary group from the chiral center at C7. This group was separated by one carbon from C7 in the first total synthesis, so the keto-auxiliary moiety could be converted to a
532:
were compared to C NMR data from model compounds. This allowed for the determination of these heteroatoms' locations in the ring, and subsequently the existence of the thiazoline ring itself. With these partial structures established, their connectivity was evaluated via
783:, in anticipation of addition of the amino alcohol immediately thereafter. In this synthesis, this keto-auxiliary group is directly adjacent to C7, necessitating a one carbon homologation, before construction of the thiazoline ring. This was achieved through reductive
433:
carbon chain, which are tertiary carbon atoms bearing three single carbon bonds and one hydrogen. The four methyl groups (each at a methine chiral center), the structure's overall stereochemistry, and the N-methyl group all contribute to the toxicity of kalkitoxin.
917:(LDH) production. The amount of LDH is a measure for neuronal cell death. In the presence of kalkitoxin there is also a concentration-dependent inhibition of neuronal cell death and LDH production (9). The mechanism behind this inhibition is still unknown.
438:
1360:
Hawkins, Clifford J.; Lavin, Martin F.; MarshallKaren A., Karen A.; Van den Brenk, Anna L.; Watters, Diane J. (1990-06-01). "Structure-activity relationships of the lissoclinamides: cytotoxic cyclic peptides from the ascidian
Lissoclinum patella".
988:
cells or normal cells. This test yielded promising results, as kalkitoxin exhibited preferential cytotoxicity for the solid tumor cell test conditions (Colon 38, and HCT-116 cells) as compared to the non-solid tumor and normal cell conditions.
651:
the leftmost segment of the molecule being critical for bioactivity. Finally, replacement of the tertiary amide with a secondary amide eliminates any observable toxicity, so this structure is crucial in the mechanism of kalkitoxin toxicity.
112:
416:
OS. The structure contains two double bonds, a 2,4-disubstituted thiazoline ring system, and an additional carbonyl-group. These four groups each provide a degree of unsaturation, which causes kalkitoxin to have four
1034:, and induces cytotoxicity in cultured rat CGNs at delayed time points. Therefore, this effect must be taken into account when considering kalkitoxin or its chemical derivatives for use as a therapeutic option.
1403:
White, James D.; Xu, Qing; Lee, Chang-Sun; Valeriote, Frederick A (2004). "Total synthesis and biological evaluation of (+)-kalkitoxin, a cytotoxic metabolite of the cyanobacterium
Lyngbya majuscula".
1067:
Berman; et al. (1999). "Antillatoxin and kalkitoxin, ichthyotoxins from the tropical cyanobacterium
Lyngbya majuscula, induce distinct temporal patterns of NMDA receptor-mediated neurotoxicity".
454:
of kalkitoxin was first determined by characterizing six partial structures which were subsequently connected to yield the total structure. This investigation was largely carried out through various
890:
This figure illustrates the two distinct interactions kalkitoxin makes with receptors in the glutamatergic synapse, and how these two interactions are oppositional at the level of neuronal survival.
2353:
971:
Many efforts to discover cancer therapeutic drugs focus on the screening of novel biomolecules produced and isolated from various plants and animals. These isolated molecules are screened via
482:
groups, then a methine group bearing a high-field methyl group. The next two groups identified (d,e) are identical and opposing strings of CH2-CH-CH3, however the left grouping's methylene
823:" synthesis approach, as opposed to the conventional iterative synthetic approach taken in previous syntheses which normally necessitate functional-group interconversions and repetitive
913:, thereby inhibiting Ca release that normally occurs when the voltage-gated sodium channel is activated, in a concentration dependent matter. Calcium release has been shown to induce
570:
534:
1217:
906:
and other excitotoxic compounds and can induce neuronal necrosis. It is not yet known if the toxin induces necrosis directly or via the release of excitotoxic compounds.
844:
producing the core aliphatic chain as a single large fragment, and coupled this fragment to the chiral sec-butyl group bearing a carboxylic acid. The opposing amino
1248:
855:
Published on Nature : Burns, M., Essafi, S., Bame, J. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–188 (2014).
478:
group. Since this is a tertiary amide, it exists in a cis/trans mixture, which underlies the two conformations of kalkitoxin. Structure (c) is a string of two
1281:
Wu; et al. (2000). "Structure, Synthesis, and
Biological Properties of Kalkitoxin, a Novel Neurotoxin from the Marine Cyanobacterium Lyngbya majuscule".
735:
of an (R)-amino alcohol, which, through two cyclodehydration steps using Wipf's oxazoline-thiazoline interconversion protocol, produces the thiazoline ring.
245:
541:
values for nonadjacent carbons and protons. This allows for the spatial relation of specific carbon and hydrogen atoms within a structure to be determined.
852:
following the procedure devised by White et al. In total, this synthesis requires only 7 steps if the initial homologation series is counted as one step.
775:
of the resulting 1,3-dimethyl configuration during the larger sequential introduction of the methyl substituents at the C7, C8 and C10 chiral centers.
824:
1580:
LePage; et al. (2005). "The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons".
763:
reaction was used instead. This was done specifically by connecting the organocopper species to a 4-phenyl-2-oxazolidinone carrying an (S)-N-trans-
975:
to measure their effects in standardized paradigms designed to select for the desired therapeutic effect. Kalkitoxin was originally isolated from
924:(ETC) complex 1, one of the protein complexes involved in mitochondrial respiration. By blocking the ETC complex 1, kalkitoxin potently inhibits
455:
229:
InChI=1S/C21H38N2OS/c1-8-16(4)21(24)23(7)11-10-15(3)12-17(5)18(6)13-20-22-19(9-2)14-25-20/h9,15-19H,2,8,10-14H2,1,3-7H3/t15-,16-,17+,18-,19-/m1/s1
1917:
1717:
1530:
Balieu; et al. (2015). "Toward
Ideality: The Synthesis of (+)-Kalkitoxin and (+)-Hydroxyphthioceranic Acid by Assembly-Line Synthesis".
1015:
which induces expression of genes promoting oxygen availability and decreasing oxygen consumption, the effect of which counteracts cellular
979:
as an effort to collect new molecules for testing as antitumor or antifungal agents. One of the first tests of kalkitoxin tumor-selective
760:
578:
1624:
356:
220:
1121:"Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling and blocks mitochondrial electron transport in tumor cells"
752:
709:
768:
732:
621:
384:
which covers sections of the coral reef. It typically forms mini-blooms and produces several metabolites, such as kalkitoxin,
2200:
680:
at C8 and C10 found in (+)-kalkitoxin, and carried a dimethylphenylsiloxy (DPSO) group positioned beta to C8, and a terminal
959:: 150-180nM ). Kalkitoxin also has been shown to have delayed neurotoxic effects on cerebellar granule cells of the rat (LC
628:
within the compound, and how those specific structures directly contribute to the extent and character of the molecule's
323:
1690:
Semenza, G.L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. 2014, 9, 47–71.
886:
168:
2489:
189:
751:. A major aspect by which this differs from the first total synthesis of (+)-kalkitoxin is that rather than using a
2066:
1757:
525:
704:, finalizing the tertiary amide which has been shown to be so crucial for kalkitoxin toxicity. O-Desilylation and
1910:
1710:
1004:
925:
474:. Structure (b) contains this carbonyl group, and an adjacent tertiary methylated nitrogen atom, constituting a
1170:
Nogle and
Gerwick (2003). "Diverse Secondary Metabolites from a Puerto Rican Collection of Lyngbya Majuscula".
1024:
996:
921:
875:
360:
668:
This effort was the first total synthesis of (+)-kalkitoxin, and served the purpose of deducing the specific
565:
nitrogen. The total stereochemistry of natural (+)-kalkitoxin is 3R,7R,8S,10S,2′R. For this determination, J
2432:
2412:
581:(E.COSY). These methods use NMR to evaluate the spin-spin coupling constants which directly relate to the
418:
2235:
914:
2499:
2494:
2427:
2422:
1903:
1884:
1703:
1219:
Novel bioactive secondary metabolites from the marine cyanobacterium
Lyngbya majuscule, Thesis (M.S.)
1012:
479:
36:
206:
2298:
1851:
972:
673:
629:
518:
78:
1325:
Umezawa; et al. (2011). "Synthesis and
Biological Activity of Kalkitoxin and its Analogues".
2417:
2378:
1785:
828:
771:
to the α,β-unsaturation of the crotonyl group. This method is advantageous because it allows for
625:
558:
451:
430:
2240:
1673:
1620:
1597:
1547:
1507:
1458:
1420:
1378:
1342:
1242:
1187:
1152:
1084:
1016:
1000:
976:
938:
772:
748:
521:
495:
380:
347:
425:, one of which is due to a substituent of the thiazoline ring, and the other four are due to
132:
2333:
2328:
2323:
2318:
2313:
2308:
2303:
2000:
1663:
1653:
1589:
1539:
1497:
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1412:
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1334:
1290:
1234:
1179:
1142:
1132:
1076:
728:
499:
268:
88:
177:
2463:
2453:
2448:
2230:
2033:
2025:
1866:
849:
788:
780:
669:
612:
differences, revealing the natural (+)-kalkitoxin stereochemistry to be 3R,7R,8S,10S,2′R.
514:
787:
of the auxiliary group to a primary alcohol and oxidation to the corresponding aldehyde,
1011:, leading to worsening disease stages and increased resistance to treatment. HIF-1 is a
603:
from the thiazoline ring and attached terminal alkene. Marfey's analysis indicated this
2468:
2458:
2283:
2010:
1856:
1794:
1502:
1477:
1147:
1120:
951:
910:
871:
713:
609:
582:
503:
487:
471:
463:
317:
1668:
1641:
1445:
White, James D; Lee, Chang-Sun; Xu, Qing (2003). "Total synthesis of (+)-kalkitoxin".
1080:
2483:
2215:
2195:
2167:
2134:
2114:
2038:
1960:
1940:
1841:
1836:
1642:"The future of cytotoxic therapy: selective cytotoxicity based on biology is the key"
1028:
899:
867:
820:
784:
764:
747:
The second total synthesis of (+)-kalkitoxin was only 16 steps and gave a 3% overall
724:
689:
685:
557:
is coordinated, with the remaining four occurring at tertiary carbon atoms along the
467:
426:
392:. Kalkitoxin has been found and purified near the coasts of Curaçao and Puerto Rico.
376:
352:
343:
157:
692:, which is the position at which (R)-2-methylbutyric acid is coupled to produce the
1995:
1990:
1955:
1861:
1816:
1752:
1020:
1008:
993:
980:
895:
833:
633:
600:
550:
422:
389:
372:
437:
1593:
723:
react to produce an alkene. In this case, a beta-keto phosphonate bearing an (R)-
2358:
2265:
2205:
2149:
2124:
2094:
2081:
2015:
2005:
1980:
1831:
1826:
1821:
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1777:
756:
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459:
401:
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2273:
2220:
2109:
2104:
2099:
2061:
2056:
2048:
1975:
1970:
1926:
1747:
1742:
1734:
1726:
796:
792:
646:
the removal of the C10 methyl group has a smaller impact on potency than does
637:
604:
596:
592:
538:
529:
510:
302:
123:
2210:
2187:
2172:
2159:
2144:
2129:
2089:
2071:
1985:
1965:
1846:
1800:
1767:
903:
845:
840:
677:
385:
1677:
1601:
1551:
1511:
1478:"High Precision Assembly Line Synthesis for Molecules with Tailored Shapes"
1462:
1424:
1346:
1191:
1156:
1088:
1007:
activation, which is crucial in solid tumor cancers because hypoxia drives
441:
The six partial structures used to derive the total structure of kalkitoxin
1382:
528:. The chemical shifts of ring carbons adjacent to the sulfur and nitrogen
2250:
2225:
2177:
2119:
1950:
1945:
985:
800:
587:
537:, a 2D NMR technique which allows for the determination of heteronuclear
1493:
1374:
848:
fragment was synthesized separately, and then adjoined and subsequently
2368:
2343:
2338:
2278:
2255:
2245:
2139:
1137:
1031:
144:
23:
1543:
1338:
1294:
1183:
856:
404:
toxin with a molecular weight of 366.604Da. Its chemical formula is C
2348:
1454:
1416:
688:
of this alkene gives the resulting alcohol, which is converted to an
681:
647:
642:
554:
483:
984:
against solid tumor cells, and either non-solid tumor cells such as
731:
group was ligated to the molecule. This group is lost in asymmetric
316:
Except where otherwise noted, data are given for materials in their
1658:
2396:
2293:
2288:
992:
Kalkitoxin exerts this cytotoxic effect through inhibition of the
804:
705:
697:
562:
491:
475:
339:
111:
101:
591:
C3 was determined by Marfey's analysis, wherein the compound was
2391:
2386:
943:
1899:
1699:
569:
values by a variation of the HSQMBC pulse technique, a type of
1895:
1695:
624:(SAR) of a molecule is the connection between the structural
2354:
Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide)
194:
894:
Kalkitoxin induces delayed neuronal necrosis in cerebellar
819:
This synthesis differentiates itself in that it takes an "
553:, one of which is the ring carbon to which the terminal
791:
using an ylide carrying a methoxy group to produce an
902:
mediated. These receptors are normally activated by
672:
of natural kalkitoxin. This synthesis began from an
2441:
2405:
2377:
2264:
2186:
2158:
2080:
2047:
2024:
1933:
1809:
1776:
1733:
708:of the resulting alcohol produce an acceptor for a
586:C10 is separated from C8 by C9, which carries two
502:from a given atom nucleus, eliciting an increased
949:: 700nM) and to aquatic crustacean brine shrimp (
359:, and induces cellular hypoxia by inhibiting the
898:of the rat. This neuronal necrosis proved to be
156:
87:
1911:
1711:
8:
1247:: CS1 maint: numeric names: authors list (
1918:
1904:
1896:
1718:
1704:
1696:
759:carrying the 4-phenyl-2-oxazolidinone, an
509:The final partial structure consists of a
131:
15:
1667:
1657:
1501:
1146:
1136:
490:, due to their proximity to the adjacent
176:
1532:Journal of the American Chemical Society
1283:Journal of the American Chemical Society
1023:(CGN) in culture. Kalkitoxin acts as an
936:Kalkitoxin is ichthyotoxic to goldfish (
885:
436:
1525:
1523:
1521:
1398:
1396:
1394:
1392:
1042:
494:. Deshielding is an effect of a nearby
253:CC(C)C(=O)N(C)CC(C)C(C)(C)CC1=N(CS1)C=C
250:
225:
205:
1440:
1438:
1436:
1434:
1240:
1575:
1573:
1571:
1569:
1567:
1565:
1563:
1561:
232:Key: PHYRFZDJEDWWKT-UJWQCDCRSA-N
7:
1405:Organic & Biomolecular Chemistry
1320:
1318:
1316:
1314:
1312:
1310:
1308:
1306:
1304:
1276:
1274:
1272:
1270:
1268:
1266:
1264:
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1258:
1211:
1209:
1207:
1205:
1203:
1201:
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1058:
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1054:
1052:
1050:
1048:
1046:
857:https://doi.org/10.1038/nature13711
462:group, indicated by characteristic
355:mediated neuronal necrosis, blocks
147:
997:electron transport chain complex 1
579:exclusive correlation spectroscopy
14:
1233:Royal Society of Chemistry 2015.
357:voltage-dependent sodium channels
1880:
1879:
999:. This causes the inhibition of
807:to produce the carboxylic acid.
753:Horner-Wadsworth-Emmons reaction
710:Horner-Wadsworth-Emmons reaction
458:experiments. Structure (a) is a
286:
280:
22:
920:Thirdly, kalkitoxin blocks the
761:organocopper conjugate addition
622:structure-activity relationship
616:Structure-activity relationship
320:(at 25 °C , 100 kPa).
2201:Tetramethylenedisulfotetramine
1363:Journal of Medicinal Chemistry
517:substituent, as determined by
295:
292:
274:
1:
1640:de Bono; et al. (2003).
1081:10.1016/s0041-0101(99)00108-7
911:voltage-gated sodium channels
636:which relies on the complete
632:. Kalkitoxin exhibits potent
1594:10.1016/j.toxlet.2005.03.007
1327:Journal of Organic Chemistry
1119:Morgan; et al. (2015).
909:Secondly, kalkitoxin blocks
872:voltage-gated sodium channel
866:Kalkitoxin may activate the
700:. The amide is subsequently
61:)-7--3,5,6-trimethylheptyl}-
1476:Burns; et al. (2014).
1172:Journal of Natural Products
839:This allows for control of
561:chain originating from the
421:. The structure contains 5
2516:
1619:. CRC Press. p. 539.
1222:. Oregon State University.
1021:cerebellar granule neurons
1875:
1617:Handbook of Cyanobacteria
684:positioned alpha to C10.
314:
261:
241:
216:
71:
35:
30:
21:
926:hypoxia-inducible factor
922:electron transport chain
876:electron transport chain
396:Structure and reactivity
361:electron transport chain
2406:Cholinergic neurotoxins
1447:Chemical Communications
1235:"ChemSpider Kalkitoxin"
446:Structure determination
419:degrees of unsaturation
1646:Breast Cancer Research
891:
836:ester building block.
442:
2433:Hemicholinium mustard
2413:Acetylcholine mustard
2236:Chlorophenylsilatrane
915:lactate dehydrogenase
889:
870:. It also blocks the
769:nucleophilic addition
440:
65:,2-dimethylbutanamide
2428:Ethylcholine mustard
1615:Sarma, T.A. (2012).
1025:N-methyl-D-aspartate
1013:transcription factor
967:Therapeutic research
767:group through a 1,4-
549:Kalkitoxin has five
506:as measured by NMR.
470:due to the adjacent
37:Preferred IUPAC name
2379:Bicyclic phosphates
2001:Spooky toxin (SsTx)
1852:Debromoaplysiatoxin
1494:10.1038/nature13711
1375:10.1021/jm00168a016
1289:(48): 12041–12042.
676:bearing the proper
630:biological activity
519:electron ionization
486:experience greater
375:, derived from the
310: g·mol
18:
2490:Ion channel toxins
1786:Cylindrospermopsin
1582:Toxicology Letters
1138:10.3390/md13031552
1009:tumor angiogenesis
892:
733:conjugate addition
443:
324:Infobox references
16:
2477:
2476:
2241:Sulfuryl fluoride
1893:
1892:
1544:10.1021/ja512875g
1538:(13): 4398–4403.
1488:(7517): 183–188.
1449:(16): 2012–2013.
1411:(14): 2092–2102.
1339:10.1021/jo201951s
1295:10.1021/ja005526y
1184:10.1021/np020332c
977:Lyngbya majuscula
939:Carassius auratus
773:stereoselectivity
595:and subsequently
571:HMBC spectroscopy
535:HMBC spectroscopy
522:mass spectrometry
498:atom withdrawing
381:Lyngbya majuscula
371:Kalkitoxin is an
363:(ETC) complex 1.
348:Lyngbya majuscula
342:derived from the
332:Chemical compound
330:
329:
190:CompTox Dashboard
113:Interactive image
2507:
1920:
1913:
1906:
1897:
1883:
1882:
1720:
1713:
1706:
1697:
1691:
1688:
1682:
1681:
1671:
1661:
1637:
1631:
1630:
1612:
1606:
1605:
1577:
1556:
1555:
1527:
1516:
1515:
1505:
1473:
1467:
1466:
1455:10.1039/B306124H
1442:
1429:
1428:
1417:10.1039/B404205K
1400:
1387:
1386:
1369:(6): 1634–1638.
1357:
1351:
1350:
1322:
1299:
1298:
1278:
1253:
1252:
1246:
1238:
1230:
1224:
1223:
1213:
1196:
1195:
1167:
1161:
1160:
1150:
1140:
1131:(3): 1552–1568.
1116:
1093:
1092:
1064:
500:electron density
400:Kalkitoxin is a
309:
297:
294:
288:
282:
276:
269:Chemical formula
209:
198:
196:
180:
160:
149:
135:
115:
91:
26:
19:
2515:
2514:
2510:
2509:
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2504:
2480:
2479:
2478:
2473:
2454:Dimethylmercury
2449:Dimethylcadmium
2437:
2423:Choline mustard
2401:
2373:
2260:
2231:Phenylsilatrane
2182:
2154:
2076:
2043:
2034:Botulinum toxin
2020:
1929:
1924:
1894:
1889:
1871:
1867:Aetokthonotoxin
1805:
1772:
1729:
1724:
1694:
1689:
1685:
1639:
1638:
1634:
1627:
1614:
1613:
1609:
1579:
1578:
1559:
1529:
1528:
1519:
1475:
1474:
1470:
1444:
1443:
1432:
1402:
1401:
1390:
1359:
1358:
1354:
1324:
1323:
1302:
1280:
1279:
1256:
1239:
1232:
1231:
1227:
1216:Wu, M. (1997).
1215:
1214:
1199:
1169:
1168:
1164:
1118:
1117:
1096:
1066:
1065:
1044:
1040:
973:in-vitro assays
969:
962:
958:
947:
934:
884:
864:
817:
789:Wittig reaction
781:carboxylic acid
745:
670:stereochemistry
666:
657:
618:
576:
568:
547:
545:Stereochemistry
515:terminal alkene
496:electronegative
466:of its central
448:
415:
411:
407:
398:
369:
367:Natural sources
333:
326:
321:
307:
291:
285:
279:
271:
257:
254:
249:
248:
237:
234:
233:
230:
224:
223:
212:
199:
192:
183:
163:
150:
138:
118:
105:
94:
81:
67:
66:
12:
11:
5:
2513:
2511:
2503:
2502:
2497:
2492:
2482:
2481:
2475:
2474:
2472:
2471:
2469:Tetraethyllead
2466:
2461:
2459:Toxopyrimidine
2456:
2451:
2445:
2443:
2439:
2438:
2436:
2435:
2430:
2425:
2420:
2415:
2409:
2407:
2403:
2402:
2400:
2399:
2394:
2389:
2383:
2381:
2375:
2374:
2372:
2371:
2366:
2361:
2356:
2351:
2346:
2341:
2336:
2331:
2326:
2321:
2316:
2311:
2306:
2301:
2296:
2291:
2286:
2284:Novichok agent
2281:
2276:
2270:
2268:
2262:
2261:
2259:
2258:
2253:
2248:
2243:
2238:
2233:
2228:
2223:
2218:
2213:
2208:
2203:
2198:
2192:
2190:
2184:
2183:
2181:
2180:
2175:
2170:
2164:
2162:
2156:
2155:
2153:
2152:
2147:
2142:
2137:
2132:
2127:
2122:
2117:
2112:
2107:
2102:
2097:
2092:
2086:
2084:
2078:
2077:
2075:
2074:
2069:
2064:
2059:
2053:
2051:
2045:
2044:
2042:
2041:
2036:
2030:
2028:
2022:
2021:
2019:
2018:
2013:
2011:Zetekitoxin AB
2008:
2003:
1998:
1993:
1988:
1983:
1978:
1973:
1968:
1963:
1958:
1953:
1948:
1943:
1937:
1935:
1931:
1930:
1925:
1923:
1922:
1915:
1908:
1900:
1891:
1890:
1888:
1887:
1876:
1873:
1872:
1870:
1869:
1864:
1859:
1857:Lyngbyatoxin-a
1854:
1849:
1844:
1839:
1834:
1829:
1824:
1819:
1813:
1811:
1807:
1806:
1804:
1803:
1798:
1795:Microcystin-LR
1788:
1782:
1780:
1774:
1773:
1771:
1770:
1765:
1760:
1755:
1750:
1745:
1739:
1737:
1731:
1730:
1725:
1723:
1722:
1715:
1708:
1700:
1693:
1692:
1683:
1659:10.1186/bcr597
1632:
1625:
1607:
1557:
1517:
1468:
1430:
1388:
1352:
1300:
1254:
1225:
1197:
1162:
1094:
1075:(11): 1645–8.
1041:
1039:
1036:
968:
965:
960:
956:
952:Artemia salina
945:
933:
930:
883:
882:Mode of action
880:
863:
860:
816:
809:
744:
737:
665:
658:
656:
653:
617:
614:
588:diastereotopic
583:dihedral angle
574:
566:
551:chiral centers
546:
543:
504:chemical shift
476:tertiary amide
447:
444:
427:methine groups
423:chiral centers
413:
409:
405:
397:
394:
377:cyanobacterium
368:
365:
344:cyanobacterium
331:
328:
327:
322:
318:standard state
315:
312:
311:
305:
299:
298:
289:
283:
277:
272:
267:
264:
263:
259:
258:
256:
255:
252:
244:
243:
242:
239:
238:
236:
235:
231:
228:
227:
219:
218:
217:
214:
213:
211:
210:
207:DTXSID80897233
202:
200:
188:
185:
184:
182:
181:
173:
171:
165:
164:
162:
161:
153:
151:
143:
140:
139:
137:
136:
128:
126:
120:
119:
117:
116:
108:
106:
99:
96:
95:
93:
92:
84:
82:
77:
74:
73:
69:
68:
40:
39:
33:
32:
28:
27:
13:
10:
9:
6:
4:
3:
2:
2512:
2501:
2498:
2496:
2493:
2491:
2488:
2487:
2485:
2470:
2467:
2465:
2462:
2460:
2457:
2455:
2452:
2450:
2447:
2446:
2444:
2440:
2434:
2431:
2429:
2426:
2424:
2421:
2419:
2416:
2414:
2411:
2410:
2408:
2404:
2398:
2395:
2393:
2390:
2388:
2385:
2384:
2382:
2380:
2376:
2370:
2367:
2365:
2362:
2360:
2357:
2355:
2352:
2350:
2347:
2345:
2342:
2340:
2337:
2335:
2332:
2330:
2327:
2325:
2322:
2320:
2317:
2315:
2312:
2310:
2307:
2305:
2302:
2300:
2297:
2295:
2292:
2290:
2287:
2285:
2282:
2280:
2277:
2275:
2272:
2271:
2269:
2267:
2263:
2257:
2254:
2252:
2249:
2247:
2244:
2242:
2239:
2237:
2234:
2232:
2229:
2227:
2224:
2222:
2219:
2217:
2216:Methamidophos
2214:
2212:
2209:
2207:
2204:
2202:
2199:
2197:
2196:Fenpropathrin
2194:
2193:
2191:
2189:
2185:
2179:
2176:
2174:
2171:
2169:
2168:Ibotenic acid
2166:
2165:
2163:
2161:
2157:
2151:
2148:
2146:
2143:
2141:
2138:
2136:
2135:Oenanthotoxin
2133:
2131:
2128:
2126:
2123:
2121:
2118:
2116:
2113:
2111:
2108:
2106:
2103:
2101:
2098:
2096:
2093:
2091:
2088:
2087:
2085:
2083:
2079:
2073:
2070:
2068:
2065:
2063:
2060:
2058:
2055:
2054:
2052:
2050:
2046:
2040:
2039:Tetanospasmin
2037:
2035:
2032:
2031:
2029:
2027:
2023:
2017:
2014:
2012:
2009:
2007:
2004:
2002:
1999:
1997:
1994:
1992:
1989:
1987:
1984:
1982:
1979:
1977:
1974:
1972:
1969:
1967:
1964:
1962:
1961:Charybdotoxin
1959:
1957:
1954:
1952:
1949:
1947:
1944:
1942:
1941:Batrachotoxin
1939:
1938:
1936:
1934:Animal toxins
1932:
1928:
1921:
1916:
1914:
1909:
1907:
1902:
1901:
1898:
1886:
1878:
1877:
1874:
1868:
1865:
1863:
1860:
1858:
1855:
1853:
1850:
1848:
1845:
1843:
1842:Cyanopeptolin
1840:
1838:
1837:Cyanobacterin
1835:
1833:
1830:
1828:
1825:
1823:
1820:
1818:
1815:
1814:
1812:
1808:
1802:
1799:
1796:
1792:
1789:
1787:
1784:
1783:
1781:
1779:
1775:
1769:
1766:
1764:
1761:
1759:
1756:
1754:
1751:
1749:
1746:
1744:
1741:
1740:
1738:
1736:
1732:
1728:
1721:
1716:
1714:
1709:
1707:
1702:
1701:
1698:
1687:
1684:
1679:
1675:
1670:
1665:
1660:
1655:
1651:
1647:
1643:
1636:
1633:
1628:
1626:9781578088003
1622:
1618:
1611:
1608:
1603:
1599:
1595:
1591:
1587:
1583:
1576:
1574:
1572:
1570:
1568:
1566:
1564:
1562:
1558:
1553:
1549:
1545:
1541:
1537:
1533:
1526:
1524:
1522:
1518:
1513:
1509:
1504:
1499:
1495:
1491:
1487:
1483:
1479:
1472:
1469:
1464:
1460:
1456:
1452:
1448:
1441:
1439:
1437:
1435:
1431:
1426:
1422:
1418:
1414:
1410:
1406:
1399:
1397:
1395:
1393:
1389:
1384:
1380:
1376:
1372:
1368:
1364:
1356:
1353:
1348:
1344:
1340:
1336:
1333:(1): 357–70.
1332:
1328:
1321:
1319:
1317:
1315:
1313:
1311:
1309:
1307:
1305:
1301:
1296:
1292:
1288:
1284:
1277:
1275:
1273:
1271:
1269:
1267:
1265:
1263:
1261:
1259:
1255:
1250:
1244:
1236:
1229:
1226:
1221:
1220:
1212:
1210:
1208:
1206:
1204:
1202:
1198:
1193:
1189:
1185:
1181:
1178:(2): 217–20.
1177:
1173:
1166:
1163:
1158:
1154:
1149:
1144:
1139:
1134:
1130:
1126:
1122:
1115:
1113:
1111:
1109:
1107:
1105:
1103:
1101:
1099:
1095:
1090:
1086:
1082:
1078:
1074:
1070:
1063:
1061:
1059:
1057:
1055:
1053:
1051:
1049:
1047:
1043:
1037:
1035:
1033:
1030:
1026:
1022:
1018:
1014:
1010:
1006:
1002:
998:
995:
994:mitochondrial
990:
987:
982:
978:
974:
966:
964:
954:
953:
948:
941:
940:
931:
929:
927:
923:
918:
916:
912:
907:
905:
901:
900:NMDA-receptor
897:
896:granule cells
888:
881:
879:
877:
873:
869:
868:NMDA receptor
861:
859:
858:
853:
851:
847:
842:
837:
835:
830:
826:
825:purifications
822:
821:assembly line
814:
810:
808:
806:
802:
798:
794:
790:
786:
785:bond cleavage
782:
776:
774:
770:
766:
762:
758:
754:
750:
742:
738:
736:
734:
730:
726:
725:phenylglycine
722:
719:
716:and an alpha-
715:
711:
707:
703:
699:
695:
691:
687:
686:Hydroboration
683:
679:
675:
671:
663:
659:
654:
652:
649:
648:epimerization
644:
639:
635:
631:
627:
623:
615:
613:
611:
606:
602:
598:
594:
589:
584:
580:
572:
564:
560:
556:
552:
544:
542:
540:
536:
531:
527:
523:
520:
516:
512:
507:
505:
501:
497:
493:
489:
485:
481:
477:
473:
469:
468:methine group
465:
461:
457:
453:
445:
439:
435:
432:
428:
424:
420:
403:
395:
393:
391:
387:
383:
382:
378:
374:
366:
364:
362:
358:
354:
353:NMDA receptor
350:
349:
345:
341:
337:
325:
319:
313:
306:
304:
301:
300:
273:
270:
266:
265:
260:
251:
247:
240:
226:
222:
215:
208:
204:
203:
201:
191:
187:
186:
179:
175:
174:
172:
170:
167:
166:
159:
155:
154:
152:
146:
142:
141:
134:
130:
129:
127:
125:
122:
121:
114:
110:
109:
107:
103:
98:
97:
90:
86:
85:
83:
80:
76:
75:
70:
64:
60:
56:
52:
48:
44:
38:
34:
29:
25:
20:
2266:Nerve agents
2082:Plant toxins
1996:Vanillotoxin
1991:Tetrodotoxin
1956:Bungarotoxin
1862:Microviridin
1817:Aplysiatoxin
1791:Microcystins
1778:Hepatotoxins
1762:
1753:Antillatoxin
1686:
1652:(3): 154–9.
1649:
1645:
1635:
1616:
1610:
1588:(2): 133–9.
1585:
1581:
1535:
1531:
1485:
1481:
1471:
1446:
1408:
1404:
1366:
1362:
1355:
1330:
1326:
1286:
1282:
1228:
1218:
1175:
1171:
1165:
1128:
1125:Marine Drugs
1124:
1072:
1068:
991:
981:cytotoxicity
970:
950:
937:
935:
919:
908:
893:
865:
854:
838:
818:
812:
803:and finally
777:
755:to ligate a
746:
740:
712:, wherein a
667:
661:
634:cytotoxicity
619:
601:cysteic acid
548:
524:(EI-MS) and
513:ring with a
508:
449:
399:
390:antillatoxin
379:
373:ichthyotoxin
370:
346:
335:
334:
72:Identifiers
62:
58:
54:
50:
46:
42:
2500:Neurotoxins
2495:Cyanotoxins
2418:Catecholine
2359:Fluorotabun
2206:Bromethalin
2150:Veratridine
2125:Ginkgotoxin
2095:Bicuculline
2049:Cyanotoxins
2016:Dendrotoxin
2006:Epibatidine
1981:Poneratoxin
1927:Neurotoxins
1832:Coibamide A
1827:Caldoramide
1822:Apratoxin A
1735:Neurotoxins
1727:Cyanotoxins
963:: 3,86nM).
757:phosphonate
721:phosphonate
698:amide group
530:heteroatoms
488:deshielding
464:deshielding
402:lipopeptide
262:Properties
89:247184-89-0
17:Kalkitoxin
2484:Categories
2364:Chinese VX
2274:Cyclosarin
2221:Endosulfan
2188:Pesticides
2160:Mycotoxins
2110:Strychnine
2105:Picrotoxin
2100:Penitrem A
2062:Guanitoxin
2057:Anatoxin-a
1976:Huwentoxin
1971:Fasciculin
1763:Kalkitoxin
1748:Guanitoxin
1743:Anatoxin-a
1038:References
797:hydrolysis
793:enol ether
718:methylated
702:methylated
696:group and
638:thiazoline
605:amino acid
599:to obtain
597:hydrolyzed
577:values by
539:J-coupling
511:thiazoline
429:along the
351:, induces
336:Kalkitoxin
303:Molar mass
178:79JC6ZX2R6
124:ChemSpider
100:3D model (
79:CAS Number
2211:Crimidine
2173:Muscarine
2145:Volkensin
2130:Cicutoxin
2090:Aconitine
2072:Saxitoxin
2026:Bacterial
1986:Saxitoxin
1966:Conotoxin
1847:Cyclamide
1801:Nodularin
1768:Saxitoxin
1003:-induced
904:glutamate
846:thioether
841:chirality
829:aliphatic
815:synthesis
805:oxidation
743:synthesis
729:auxiliary
727:-derived
706:oxidation
694:sec-butyl
678:chirality
664:synthesis
655:Synthesis
559:aliphatic
480:methylene
460:sec-butyl
452:structure
431:aliphatic
386:curacin-A
2251:Schradan
2226:Fipronil
2178:Muscimol
2120:Rotenone
1951:Birtoxin
1946:Bestoxin
1885:Category
1678:12793897
1602:16039402
1552:25625684
1512:25209797
1463:12934887
1425:15254638
1347:22111947
1243:cite web
1192:12608852
1157:25803180
1089:10482399
1029:receptor
986:leukemia
932:Toxicity
874:and the
850:cyclized
834:benzoate
801:aldehyde
765:crotonyl
714:carbonyl
626:moieties
593:ozonized
472:carbonyl
158:11176051
2369:EA-2192
2344:EA-4056
2339:EA-3990
2279:EA-3148
2256:Dimefox
2246:Mipafox
2140:Thujone
1503:4167605
1383:2342056
1148:4377999
1069:Toxicon
1032:agonist
1027:(NMDA)
1017:hypoxia
1001:hypoxia
862:Targets
811:Balieu
799:to the
674:alcohol
643:epimers
573:, and J
484:protons
145:PubChem
133:9351143
2349:T-1123
1793:(e.g.
1676:
1669:165009
1666:
1623:
1600:
1550:
1510:
1500:
1482:Nature
1461:
1423:
1381:
1345:
1190:
1155:
1145:
1087:
813:et al.
741:et al.
739:White
682:alkene
662:et al.
555:alkene
308:366.61
246:SMILES
31:Names
2442:Other
2397:IPTBO
2299:Tabun
2294:Soman
2289:Sarin
2115:Tutin
1810:Other
1005:HIF-1
749:yield
690:azide
610:shift
563:imine
526:C NMR
492:imine
340:toxin
221:InChI
102:JSmol
2464:IDPN
2392:TBPO
2387:TBPS
2067:BMAA
1758:BMAA
1674:PMID
1621:ISBN
1598:PMID
1548:PMID
1508:PMID
1459:PMID
1421:PMID
1379:PMID
1343:PMID
1249:link
1188:PMID
1153:PMID
1085:PMID
955:, LC
827:for
620:The
450:The
388:and
338:, a
169:UNII
49:-{(3
1664:PMC
1654:doi
1590:doi
1586:158
1540:doi
1536:137
1498:PMC
1490:doi
1486:513
1451:doi
1413:doi
1371:doi
1335:doi
1291:doi
1287:122
1180:doi
1143:PMC
1133:doi
1077:doi
660:Wu
456:NMR
195:EPA
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