1. An isolated polynucleotide selected from the following polynucleotides:
(a) a polynucleotide represented by any one of SEQ ID NOs: 1 to 11;
(b) a polynucleotide encoding a NF-YB polypeptide derived from Jatropha, comprising a polynucleotide fragment represented by SEQ ID NO: 12 or 13; and
(c) a polynucleotide represented by a nucleotide sequence having a homology of 90% or higher with the nucleotide sequence of the polynucleotide of either one of (a) and (b), wherein a polypeptide encoded by the polynucleotide maintains dry stress resistance of the NF-YB polypeptide encoded by either one of the polynucleotides of (a) and (b).
2. The isolated polynucleotide according to claim 1, selected from the polynucleotides of (a) and (b).
3. An isolated NF-YB polypeptide selected from the following polypeptides:
(a) a NF-YB polypeptide having an amino acid sequence represented by any one of SEQ ID NOs: 14 to 24;
(b) a NF-YB polypeptide derived from Jatropha comprising a polypeptide having an amino acid sequence represented by SEQ ID NO: 25 or 26; and
(c) a polypeptide represented by an amino acid sequence having a homology of 90% or higher with the amino acid sequence of the polypeptide of either one of (a) and (b), wherein the polypeptide maintains dry stress resistance of either one of the NF-YB polypeptides of (a) and (b).
4. The isolated NF-YB polypeptide according to claim 3, selected from the polypeptides of (a) and (b).
5. A polynucleotide encoding the polypeptide according to claim 3.
6. A Jatropha plant transformation vector, wherein the polynucleotide according to claim 1 is incorporated.
7. A transformant containing the vector according to claim 6.
8. A Jatropha plant transformed by using the vector according to claim 6, wherein the plant is dry stress resistant transformed Jatropha capable of overexpressing a NF-YB polypeptide compared with a wild type.
9. A seed harvested from the dry stress resistant transformed Jatropha according to claim 8.
10. A method of producing a Jatropha oil by squeezing the seed according to claim 9 and purifying it.
11. A Jatropha oil produced by the production method according to claim 10.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1-41. (canceled)
42. A method of increasing the number of functional ABC transporters in a membrane of a cell, comprising the step of contacting said cell with a compound having formula IIIB:
wherein:
X9 is CH2, CF2, CH2\u2014CH2, or CF2\u2014CF2;
m is 0 to 4;
Ht1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH;
x, q, and z is independently 0-5;
Q-RQ, X\u2014RX and Z\u2014RZ each is independently R\u2032;
L is a bond, O, S, SO, SO2, C(O), NR\u2032, C1-4 aliphatic, or CHRL;
RL is \u2014OR\u2032, \u2014SR\u2032, \u2014SOR\u2032, \u2014SO2R\u2032, or \u2014N(R\u2032)2; or
wherein ring A\u2032 is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A\u2032 is optionally substituted with q occurrences of -QRQ;
Ar is phenyl or a six-membered heteroaromatic ring;
R\u2032 is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R\u2032 are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
R\u2032 is independently R1, R2, R3, R4, or R5;
R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y; or two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy, 1,2-difluoromethylenedioxy, 1,2-ethylenedioxy, or 1,2-tetrafluoroethylenedioxy;
n is 0 or 1;
Y is halo, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SR6, SR5, S(O)R6, S(O)R6, SO2R6, SO2R5, SO2N(R6)2, SO2N(R5)2, SO2NR5R6, SO3R6, SO3R5, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2N(R6)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, N(OR5)R6;
R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n\u2014Z\u2032;
Z\u2032 is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-aliphatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic; and
R8 is an amino protecting group.
43. The method of claim 42, wherein the ABC transporter is CFTR.
44-46. (canceled)
47. A method of treating a condition, disease, or disorder in a patient implicated by ABC transporter activity, comprising the step of administering to said patient a compound having formula IIIB:
wherein:
X9 is CH2, CF2, CH2\u2014CH2, or CF2\u2014CF2;
m is 0 to 4;
Ht1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, N, or NH.
x, q, and z is independently 0-5;
Q-RQ, X\u2014Rx and Z\u2014RZ each is independently R\u2032;
L is a bond, O, S, SO, SO2, C(O), NR\u2032, C1-4 aliphatic, or CHRL;
RL is \u2014OR\u2032, \u2014SR\u2032, \u2014SOR\u2032, \u2014SO2R\u2032, or \u2014N(R\u2032)2; or
L is
wherein ring A\u2032 is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, N, or NH, wherein ring A\u2032 is optionally substituted with q occurrences of -QRQ;
Ar is phenyl or a six-membered heteroaromatic ring;
R\u2032 is independently selected from hydrogen or an optionally substituted group selected from a C1-C8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R\u2032 are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
R\u2032 is independently R1, R2, R3, R4, or R5;
R1 is oxo, R6 or ((C1-C4)aliphatic)n-Y; or two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy, 1,2-difluoromethylenedioxy, 1,2-ethylenedioxy, or 1,2-tetrafluoroethylenedioxy;
n is 0 or 1;
Y is halo, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6 or OR6;
R2 is aliphatic, wherein each R2 optionally comprises up to 2 substituents independently selected from R1, R4, or R5;
R3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R1, R2, R4 or R5;
R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), SR6, SR5, S(O)R6, S(O)R6, SO2R6, SO2R5, SO2N(R6)2, SO2N(R5)2, SO2NR5R6, SO3R6, SO3R5, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR5C(O)R6, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R6, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2N(R6)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, N(OR5)R6;
R5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R1 substituents;
R6 is H or aliphatic, wherein R6 optionally comprises a R7 substituent;
R7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH2)n\u2014Z\u2032;
Z\u2032 is selected from halo, CN, NO2, CF3, OCF3, OH, S-aliphatic, S(O)-aliphatic, SO2-alipatic, NH2, NH-aliphatic, N(aliphatic)2, N(aliphatic)R8, NHR8, COOH, C(O)O(-aliphatic), or O-aliphatic; and
R8 is an amino protecting group.
48. The method according to claim 47, wherein said condition, disease, or disorder is selected from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell diseasepseudo-Hurler, mucopolysaccharidoses, SandhofTay-Sachs, Crigler-Najjar type II, polyendocrinopathyhyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick’s disease, several polyglutamine neurological disorders asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic dystrophy, spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease, or Sj\xf6gren’s Syndrome.
49-51. (canceled)
52. The method of claim 47, wherein two R\u2032 in N(R\u2032)2 taken together with the nitrogen atom, form an optionally substituted 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S.
53. The method of claim 47, wherein m is 0.
54. The method of claim 47, wherein Ht, is a thiazolyl ring, wherein Ht is optionally substituted with up to three substituents.
55. The method of claim 47, wherein X9 is CH2.
56. The method of claim 47, wherein X9 is CF2.
57. The method of claim 47, wherein L is \u2014CH2\u2014.
58. The method of claim 47, wherein L is \u2014CH\u2014RL, wherein RL is \u2014OH, \u2014NHRD, or NRAARBB; wherein
each of RAA, RBB, and RD is independently hydrogen, C1-C6 aliphatic, C3-C7 cycloalkyl, (C3-C7-cycloalkyl)-C1-C6 aliphatic, (C3-C7-cycloalkenyl)-C1-C6-aliphatic, (3-7-membered heterocyclyl), (3-7-membered heterocyclyl)-C1-C6-aliphatic, 3-6 membered heteroaryl, (3-6-membered heteroaryl)-C1-C6 aliphatic, wherein said aliphatic, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted with up to three substituents selected from OH, \u2014O(C1-4aliphatic), or (C1-C4 aliphatic)p-Y; wherein
p is 0 or 1;
Y is OR or NHC(O)R;
R is hydrogen or C1-4 aliphatic; or
RAA and RBB, taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C1-C4 aliphatic)p-Y; and
wherein up to two methylene groups in any said aliphatic above are optionally and independently replaced with O, C(O), or NH.
59. The method of claim 58, wherein RD is hydrogen.
60. The method of claim 58, wherein RD is optionally substituted C1-C6 aliphatic.
61. The compound according to claim 18, wherein RD is selected from C1-C6 alkyl, optionally substituted with up two substituents selected from OH, \u2014O(C1-C4 alkyl), acetamido, NH2, NH(C1-C4 alkyl), or N(C1-C4 alkyl)2.
62. The method of claim 58, wherein RD is selected from an optionally substituted C3-C6 cycloalkyl or cycloalkenyl ring, or (C3-C6 cycloalkyl or cycloalkenyl ring)-C1-C6 aliphatic.
63. The method of claim 58, wherein RD is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenylethyl or cyclohexylmethyl.
64. The method of claim 58, wherein RD is selected from optionally substituted 3-7 membered heterocyclyl or (3-7 membered heterocyclyl)-C1-C6 aliphatic, wherein said heterocyclyl contains up to 2 heteroatoms selected from O, S, or N.
65. The method of claim 58, wherein RD is selected from (N-methyl-pyrrolidin-2-yl)-ethyl, pyrrolidin-1-yl-ethyl, tetrahydrofuran-2-yl-methyl, morpholin-4-yl-ethyl, or morpholin-4-yl-propyl.
66. The method of claim 58, wherein RD is selected from optionally substitued 5-6 membered heteroaryl or (5-6-membered heteroaryl)-C1-C6 aliphatic, wherein said heteroaryl contains up to 2 heteroatoms selected from O, S, or N.
67. The method of claim 58, wherein RD is selected from imidazolylpropyl, furanylmethyl, or pyridinylethyl.
68. The method of claim 58, wherein RD is selected from C1-4 alkyl optionally substituted with \u2014OH, \u2014O(C1-4alkyl), NH(C1-4 alkyl), or N(C1-4 alkyl)2.
69. The method of claim 58, wherein RD is selected from C1-4 alkyl optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo, (C1-4 aliphatic), (C1-4 aliphatic)-Y, wherein Y is halo, \u2014OH, or \u2014O(C1-4 alkyl).
70. The method of claim 58, wherein RD is selected from C1-6 alkyl optionally substituted with \u2014OH or \u2014O(C1-4alkyl).
71. The method of claim 58, wherein one of RAA and RBB is C1-C4 alkyl, and the other of RAA and RBB is selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)-C1-C4 alkyl, wherein said alkyl, alkenyl, or cycloalkenyl has up to 2 substituents selected from OH or \u2014O(C1-C4 alkyl).
72. The method of claim 58, wherein RAA and RBB, taken together with the nitrogen atom, forms a ring selected from pyrrolidinyl, piperidinyl, or morpholinyl, wherein said ring is optionally substituted with up to two substituents selected from hydroxy, C1-C4 alkyl, C2-C4 alkenyl, COOH, acetoxy, acetyl, hydroxymethyl, methoxymethyl, hydroxyethyl, methoxyethyl, allyl, ethylenedioxy, or C(O)NH2.
73. The method of claim 58, wherein said compound has formula VB-3-i:
wherein X9 is CH2 or CF2;
RAA and RBB are selected from hydrogen, C1-C6 alkyl, or \u2014CH(C1-C6 alkyl)-CH2OH; or
RAA and RBB taken together form a pyrrolidinyl ring optionally substituted with (C1-C4 aliphatic)p-Y.
74. The method of claim 73, wherein RAA and RBB taken together is 3-acetoxy-pyrrolidin-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, 2-hydroxymethyl-pyrrolidin-1-yl, (2-carboxypyrrolidin-1-yl), pyrrolidin-1-yl, 2-aminocarbonyl-pyrrolidin-1-yl, or 3-hydroxy-pyrrolidin-1-yl.
75. The method of claim 73, wherein RAA is hydrogen, and RBB is \u2014CH(C1-C6 alkyl)-CH2OH.
76. The method of claim 75, wherein said alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or isobutyl.
77. The method of claim 75, wherein said RBB is (R)\u2014CH(C1-C6 alkyl)-CH2OH or RBB is (S)\u2014CH(C1-C6 alkyl)-CH2OH.
78. The method of claim 47, wherein the compound selected from the following table:
Cmpd
#
Compound
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
79. The method of claim 47, wherein XRX is hydrogen.
80. The method of claim 47, where
in ZRZ is selected from halo, CF3, OCF3, C1-C4 alkoxy, methylenedioxy, or difluoromethylenedioxy.
81. The method of claim 47, wherein z is 1-3.
82. The method of claim 47, wherein the compound is