DSCN4999

SECONDARY METABOLITES WITH CYTOTOXIC AND ANTITUMOR ACTIVITY: PLANTS AND MICROORGANISMS

Plants and microorganisms are rich sources of metabolites possesed many biological activities, one of the most popular is antitumor activity. This review consist of two parts: plants and microorganisms, which each parts explain metabolites that was isolated and assayed to possesed antitumor activity and cytotoxic.

Part I. Plants

Astins A, B and C (Asterin)

Astins A, B, C(Asterin) are compositae-type cyclopeptides which was isolated from the roots of Aster tataricus (Compositae). Compositae-type cyclopeptides are halogenated cyclic pentapeptides containing one chlorinated proline, allo-threonine (allo-Thr), β-phenylalanine (β-Phe), α-aminobutyric acid (Abu) and serine (Ser) with one cis configuration in the proline peptide bond. Their structures are very similar to that of cyclochlorotine, a toxic principle isolated from Penicillium islandicum.[1]

Astin A (C25H33N5O7Cl2) as colorless needles, mp. 192-194°,  -77.0° (CH3OH, c 0.37). Astin B (C25H33N5O7Cl2) as colorless needles, mp. 183-185°,  -84.9° (CH3OH, c 0.31).[2] Astin C (C25H33N5O6Cl2) as colorless needles, mp. 183-187°,  -65.4° (CH3CH2OH, c 0.11).[2,3] Asterin gave positive Beilstein and Dragendorff tests.[1]

Itokawa and co-workers investigated the chemical conversion and a hepatic microsomal biotransformation in rats of astins. Results suggested that 1,2-cis dichlorinated proline residues of astins A, B and C play an important role in the antitumor activity.[4] They also reported that the produced thioastins after replacing the serine amide bonds in astins A, B and C with thioamide bonds showed more promising antitumor activities than their parents compounds.[5]

2-Acetoxy-3-hydroxy-labda-8(17),12(E),14-triene, 3-acetoxy-2-hidroxy-labda-8(17),12(E),14-triene, and 2,3-dihydroxy-labda-8(17),12(E),14-triene

The compounds are labdane diterpenoids was isolated from crude extract of the stem bark of Croton oblongifolius Roxb. (Euphorbiaceae), which has been used as a traditional medicine for many applications such as for dysmenorrhea, as a purgative and to treat dyspepsia and dysenteria. Moreover, this plant has been used in conjunction with C. sublyratus to treat gastric ulcers and gastric cancers.[6]

2-Acetoxy-3-hydroxy-labda-8(17),12(E),14-triene as white solid, m.p. 102-103°C, +50.17 (CHCl3; c 1.0) showed weak activity against gastric and colon adenocarcinoma.[6] 3-acetoxy-2-hidroxy-labda-8(17),12(E),14-triene as white solid, mp. 99-101°C, +9.46 (CHCl3; c 1.0) showed weak activity against gastric and breast ductol carcinoma.[6] 2,3-dihydroxy-labda-8(17),12(E),14-triene as white solid, m.p. 69-70°C, -6.96 (CHCl3; c 1.0) showed non-specific moderate cytotoxicities against human gastric carcinoma, colon adenocarcinoma, breast ductol carcinoma, liver hepatoblastoma and undifferentiated lung carcinoma.[6]

Bouvardin, Deoxybouvardin, and 6-O-Methylbouvardin

The compounds belonging to Rubiaceae-type cyclopeptides, which are homodicyclohexapeptides formed with one D-α-alanine (rarely D-α-aminobutyric acid), one N-methyl-L-α-alanine, three modified N-methyl-L-α-tyrosines (rarely one modified N-methyl-D-tyrosine) and one other protein L-α-amino acid. The most unusual feature is a 14-membered ring formed by oxidative coupling of the phenolic oxigen of one tyrosine with a carbon ortho to the phenolic hydroxyl group of an adjacent tyrosine with a cis peptide bond, the molecular models indicated that the 14-membered ring, which also contains a paracyclophane and a metacyclophane ring system, possesses some angle strain and very little flexibility.[1]

Bouvardin and deoxybouvardin was isolated from Bouvardia ternifolia (Rubiaceae) stems, leaves and flowers. Bouvardin (C40H48N6O10) as colorless needles, mp 254-255, -181° (CHCl3, c.1.0) has bioactivity as antitumor.[7,8] Deoxybouvardin (C40H48N6O9) as colorless powder, mp 237-240, -138° (CHCl3, c 0.7) has bioactivity as antitumor.[7,8,9] Both compounds gave a positive test with chlorine-o-toluidine reagent.[7]

Compoun d 6-O-methylbouvardin was isolated from the roots of Rubia cordifolia and R. akane (roots, stems and flowers), which belonging to family Rubiaceae. 6-O-methylbouvardin (C41H50N6O10), MW=786 as colorless plates, mp 244-247, -191° (CHCl3, c 1.0) has bioactivity as antitumor.[8]

Budlein A

The sesquiterpene lactone, budlein A is the main constituent of the sunflower-like plant Viguiera robusta (Asteraceae).[10]

Cherimolacyclopeptides A and B

The compounds belonging to Caryophyllaceae-type cyclopeptides, which are homomonocyclopeptides formed with the peptide bonds of protein or non-protein α-amino acids, which include cyclic di-, penta-, hexa-, octa-, nona-, deca-, undeca-, and dodecapeptides.[1] Cherimolacyclopeptides A and B was isolated from the seeds of Annona cherimola (Annonaceae). Cherimolacyclopeptide A (C38H63N9O10S) as colorless solids, mp 192-193, -8.5° (CH3OH, c 0.9) and cherimolacyclopeptide B (C38H63N9O11S) as colorless solids, mp 228-299, -8.3° (CH3OH, c 0.2). Both compounds have bioactivity as cytotoxic agent.[11]

Cycloleonuripeptides B and C

Cycloleonuripeptides B and C belonging to Caryophyllaceae-type cyclopeptides was isolated from the fruits of Leonurus heterophyllus (Labiatae).[1,12,13] Cycloleonuripeptide B (C47H67N9O11S) as colorless powder, -153.6° (CH3OH, c 0.98) as cytotoxic agent. Cycloleonuripeptide C (C47H67N9O11S) as colorless powder, -170.5° (CH3OH, c 0.60) has cytotoxic activity.[12,13]

Dianthin E

Dianthin E belonging to Caryophyllaceae-type cyclopeptides [1] was isolated from the whole plants of Dianthus superbus (Caryophyllaceae). Dianthin E (C30H44N607) as pale yellow powder, -30.5° (CH3OH, c. 0.02) has activity as cytotoxic agent.[14]

Dicentrine and nor-Dicentrine

Dicentrine and nor-dicentrine are aporphine alkaloids were isolated from etanolic extracts of the leaves of Ocotea acutifolia (Nees) Mez. (Lauraceae). Mixture of dicentrine and leucoxine, an aporphine alkaloids also isolated from O. acutifolia exhibited weak cytotoxicity with IC50 value of 43.78 µmL-1. Mixture of nor-dicentrine and ocoteine, an aporphine alkaloids also isolated from O. acutifolia displayed significant cytotoxicity with IC50 value of 10.08 µmL-1.[15]

Dichotomins A-C, E, H and I

Dichotomins belonging to Caryophyllaceae-type cyclopeptides  was Isolated from the roots of Stellaria dichotoma var. lanceolata (Caryophyllaceae).[1,16] Dichotomin A (C35H48N6O8) as colorless needles, mp 179-180, +14.0° (CH3OH, c 0.10). Dichotomin B (C34H46N6O9) as colorless powder, +16.0° (CH3OH, c 0.10). Dichotomin C (C33H44N6O8) as colorless powder, +34.0° (CH3OH, c 0.10). Dichotomin E (C26H31N5O6) as colorless powder, -66.7° (CH3OH, c 0.11). The four compounds have cytotoxic effects.[16] Dichotomin H (C47H66N8O10) as colorless powder, -77.5° (CH3OH, c 0.93). Dichotomin I (C49H70N8O10) as colorless powder, -99.6° (CH3OH, c 0.54) as cytotoxic agent. Both compounds also have cytotoxic effects.[17]

Duguetine β-N-oxide

Duguetine β-N-oxide was isolated from Duguetia furfuracea (Annonaceae) is a shrub distributed throughout the Brazilian state of Mato Grosso do Sul. It is known as “araticum-seco” and in folk medicine its powdered seeds are mixed with water for use against pediculosis, whereas an infusion of the twigs and leaves are used to treat rheumatism.[18] Duguetine β-N-oxide is aporphinic alkaloid and has N-methyl substituent making its structure very non-planar and would seem to make it poor candidate for DNA binding by intercalation, but cytotoxic assay has shown that this compound has potent against colon, glioblastoma and breast human cancer cells.[19]

Integerrimides A and B

Integerrimides A and B  are new cyclic heptapeptides were isolated from CH2Cl2 extracts of the latex of Jatropha integerrima Jacq. (syn. J. pandurifolia Andr.) which is a shrubby tree of which the medicinal properties have not been reported. Its latex is however known to be toxic. The leaves, if accidentally chewed can cause squeamish, stomachalgia and can be very purgative. Both peptides at 50 µM inhibited to a certain degree cell proliferation of human ICP-298 melanoma cells, as well as cell, migration of human Capan II pancreatic carcinoma cells.[20]

Jatrophone

Jatrophone, a diterpenoid was isolated from the roots Jatropha elliptica and J. gossypifolia belonging to family Euphorbiaceae. It has shown reaction of biological thiols (inhibition tumor activity)[21] and antileukemic activity against P-388 lymphocytic leukemia at 27 and 12 mg/kg cytotoxicity (ED50) against KB cell culture at 0.17 µg/ml.[22]

J. elliptica Muell. Arg., a shrub annual herb distributed throughout the North and the West of Brazil and has been reported to possess several medicinal properties.[23,24,25] J. elliptica is used in the folk medicine for treatment of neoplasia, inflammation, ulcers and diuretic diseases among others.[25] The ethanolic extract of root has shown molluscicidal activity.[26]

J. gossypifolia (synonym: Adenoropium gossypifolia Pohl, J. elegans) belonging to the family Euphorbiaceae[27] is a shrub herb, height 1.8 meter, gregarious with palmately 3-5 lobed leaves and dark red, crimson or purplish flowers. Leaf margins, petioles and stipules are covered with glandular hairs.[28] J. gossypifolia is grows naturally almost entire tropical area in the world.[29] This plant is a native of Brazil, naturalized in many parts of India. It grows on nearly all type of soils within its range. It is common in waste lands, roadsides, poorly tended agricultural fields and river overflow area.[30] Another opinion said that J. gossypifolia is native to the Carribean and tropical America but is now widespread throughout the tropical world. It has been listed as a weed in India, Brazil, Jamaica and Trinidad.[31] Flowering in India occurs from February through July. Sometimes both flowers and fruits will be present at the same time on plant. Upon drying, the capsule valves spring open propelling the seeds a few centimeters.[30]

J. gossypifolia is reported to be beneficial to dyscrasia, anemia, vertigo and dysphonia.[27] It is an antibiotic, insecticidal and used in toothache and act as blood purifier.[32] The leaves are employed to carbuncles, eczema and itches, act as purgative and swollen. A decoction of the leaves is useful for stomachache, venereal disease and as blood purifier.[33] The leaves, either in decoction or boiled like spinach, as a purgative remedy for ‘dry belly-ache’. It is used to prepare tea for constipation, the part used not being specified but it is probably the leaves.[34] Extracts of the plant are used as a purgative and emetic, and to treat headache, diarrhea, venereal disease, skin sores, mouth sores and cancer.[29] The seed are used to purgative, its oil similar to Castrol oil (Jatropha).[34] The use of the seeds in herbal medicine is advised against because of their high toxicity.[35] The seed oil is used as an emetic, purgative and stimulant. It is also applied for ulcers and leprosy and is beneficial in adenites and worm infestation.[28] The roots are recommended for leprosy and as an antidote for snake bite.[27]

Ocoteine and Ocoteine N-oxide

Ocoteine and ocoteine N-oxide are aporphine alkaloids were isolated from etanolic extracts of the leaves of Ocotea acutifolia (Nees) Mez. (Lauraceae). Ocoteine and mixture of nor-dicentrrine and ocoteine displayed significant cytotoxic activity with IC50 values of 8.14 and 10.08 µmL-1, respectively. Whilst ocoteine N-oxide exhibited weak cytotoxicity with IC50 value of 32.75 µmL-1.[15]

Podacycline B

Podacycline B was isolated from the latex of J. podagrica (Euphorbiaceae),[36] which was found to possess high cytotoxicity against Dalton’s lymphoma ascites (DLA) and Ehrlich’s ascites carcinoma (EAC) cell lines with IC50 values of 13.2 and 15.5 µM.[37]

RAs (Rubiaceae-type Cyclopeptides)

RAs belonging to Rubiaceae-type Cyclopeptides were RA-I, RA-II, RA-III, RAI-III, RA-IV, RA V (Deoxybouvardin), RA-VI, RAI-VI, RA-VII, which were isolated from the roots of Rubia cordifolia, RA-VIII, RA-IX, RA-X, RA-XI, RA-XII, which were isolated from the roots of R.  akane, and RA-XIII, RA-XV, RA-XVI, RA-XVI I which were isolated from the roots of R. yunnanensis.[38]

RA-V (Deoxybouvardin) exhibited significant activity against leukemias and ascites tumors, P-388, L1210, B-16 melanoma and solid tumors, colon 38, Lewis lung carcinoma and Ehrlich carcinoma.[38] RA-XII, RA-XIII, RA-XV dan RA-XVI are cyclopeptide glucosides discovered in higher plants for the first time.[38] RA-VIII was reported to have undergone phase I clinical trials at the NCI as an anticancer drug in Japan in 1990s, whose therapeutic ratio was 400.9.[39]

RA-I (C40H48N6O10) as colorless powder, mp 284 (dec.), -216° (CHCl3-CH3OH (9:1), c 0.08).[40] RA-II (C39H46N6O9) as colorless needles, mp. 261 (dec.), -201° (CHCl3, c 0.1).[40] RA-III (C41H50N6O10) as colorless needles, mp>300, -199° (CHCl3, c 0.1).[40] RAI-III (C41H50N6O10) as colorless needles, mp 209-211, -38.3° (CHCl3, c 0.12).[41] RA-IV (C40H48N6O10) as colorless needles, mp 247-255, -126° (CHCl3, c 0.7).[40] RA-VI (C41H50N6O10) as colorless needles, mp 219-220, -118.6° (CHCl3, 0.68).[42] RAI-VI (C41H50N6O10) as colorless needles, mp 200-202, -129.4° (CHCl3, c 0.17).[41] RA-VII (C41H50N6O9) as colorless needles, mp>300, -229° (CHCl3, c 0.1).[9,43,44] RA-VIII (C42H52N6O10) as colorless needles, mp 267-269, -159.5° (CHCl3, c 0.39).[42] RA-X (C43H52N6O11) as colorless needles, mp 254.5-255.5, -205.4° (CHCl3:CH3OH (1:1), c 1.43).[45] RA-XI (C42H50N6O11) as colorless needles, mp 255.5, -235.8° (CH3OH, c 0.24).[46] RA-XII (C46H58N6O14) as amorphous powder, mp 252-255, -270.0° (CH3OH, c 0.2).[46,47,48] RA-XIII (C48H60N6O16) as amorphous powder, mp 273-276, -109.3° (CH3OH, c 0.08).[46] RA-XV (C48H60N6O15) as needles, mp 218-220, -202.4° (CH3OH, c 0.2).[49] RA-XVI (C48H60N6O16) as needles, mp 220 (dec.), -179.7° (CH3OH, c 0.06).[49] RA-XVI I (C41H50N6O9) as amorphous powder, -194° (CHCl3, c 0.01).[50]. These sixteen RAs have antitumor activities.[40,41,42,43,44,45,46,47,48,49,50] Only RA-IX (C43H50N6O10) as colorless needles, mp 242-243, -158.1° (CHCl3, c 0.94)has potent as cytotoxic agent.[45]

Segetalin E (Vaccarin C)

Segetalin E (Vaccarin C) also belonging to Caryophyllaceae-type cyclopeptides was isolated from the seeds of Vaccaria segetalis (Caryophyllaceae).[1,51,52] Segetalin E (C43H56N8O8) as needles, mp 166-168, -59° (CH3OH, c 0.4) as cytotoxic agent.[51,52]

Yunnanins A-D

Yunnanins A-D belonging to Caryophyllaceae-type cyclopeptides was isolated from the roots of Stellaria yunnanensis (Caryophyllaceae). [1,53,54,55,56] Yunnanin A (C34H41N7O8) as colorless needles, mp 197-199 (dec.), -21.1° (CH3OH, c 0.56).[53,54,55,56] Yunnanin B (C32H42N6O8) as colorless needles, mp 151-153, +12.5° (CH3OH, c 1.70).[53,55] Yunnanin C (C36H47N7O9) as colorless needles, mp 255, -48.1° (CH3OH, c 0.21).[53,56] Yunnanin D (C40H56N10O8) as colorless powder, -20.0° (CH3OH, c 0.60).[57 ]These four cyclopeptides have bioactivity as cytotoxic agent.[53,54,55,56,57]

Zerumbone

Zerumbone, a monocyclic sesquiterpene from rhizomes of edible plant Zingiber zerumbet Smith.[58] It has recently been found to suppress tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced EpsteinBarr virus activation in a patent manner.[59]

Zingiber zerumbet Smith locally known as lempoyang wild ginger belongs to Zingiberaceae family. It is native to South East Asia but has been widely cultivated plant in village gardens throughout the tropical and subtropical area around the world and has naturalized in some areas for its medicinal properties.[60,61,62] It used in local traditional medicine as a cure for swelling, sores and loss of appetite. Besides that the juice of the boiled rhizomes has also been used as a medicine for worm infestasion in children. The volatile oils of the rhizomes have been shown to contain zerumbone, humulene and camprene.[63]

Part II. Microorganisms

Aspochalamins A-D

Aspochalamins A-D produced by Aspergillus niveus LU 9575, which grown endosymbiotic of gut from a Trichoniscidae.[64,65]

Aspochalasin Z

Aspochalamins Z produced by Aspergillus niveus LU 9575 along with Aspochalamins A-D.[64,65]

Caboxamycin

Caboxamycin, a novel benzooxazol-derived metabolit produced by Streptomyces strain NTK 937 which was isolated from sediment collected in the Canary Basin (-3814m).[66]

Elloxazinones A and B

Elloxazinones A and B, new aminophenoxazionone antibiotics produced by Streptomyces griseus Acta 2871, a terrestrical microorganism was isolated from steel waste tip soil found in Consett, UK.[67]

Fluostatins C-E

Fluostatins C-E produced from Streptomyces lavendulae Acta 1383, a terrestrical microorganism was isolated from rhizosphere in Kaisariani area, Greece.[68]

Fogacin

Fogacin produced by Streptomyces sp. Tü 6319, a terrestrical microorganism was isolated in Fogaras, Romania.[69]

Galtamycin B

Galtamycin B produced by Micromonospora sp. Tü 6368, a terrestrical microorganism was isolated in Rety, Roma.[70,71]

Genoketides A1 and A2, Prechrysophanol-Glucuronide and Chrsophanol-Glucoronide

Compounds are produced by Streptomyces sp. AK 671, a terrestrical microorganism was isolated in Hamsterley Forest, Northumberland, UK.[72]

Lactonamycin Z

Lactonamycin Z produced by Streptomyces sanglieri AK 6239, a terrestical microorganism was isolated in Hamsterley Forest, UK.[73,74]

Natoxazole

Natoxazole produced by from Streptomyces sp. Tü 6176, a terrestrical microorganism was isolated in Natal, Brazil.[75]

Polyketomycin

Polyketomycin produced by Streptomyces diastatochromogenes Tü 6028, a terrestrical microorganism was isolated in Iguaçu, Argentina.[76]

Proximicins A, B and C

Compounds are produced by Verrucosispora sp. MG-37, a marine microorganism was isolated from sediment collected in Raune Fjord, Norway.[77,78]

Pyrocoll

Pyrocoll produced by the novel alkaliphilic Streptomyces sp. AK 409, a terrestrical microorganism was isolated from steel waste tip oil found in Consett, UK.[79]

Retymicin

Retymicin was isolated from Micromonospora sp. Tü 6368, a terrestrical microorganism was isolated in Rety, Romania.[70,71]

Ripromycin

Ripromycin produced by Streptomyces sp. Tü 6239, a terrestrical microorganism was isolated in São José do Rio Preto, Brazil.[80]

Saquayamycin Z

Saquayamycin Z was isolated from Micromonospora sp. Tü 6368, a terrestrical microorganism was isolated in Rety, Romania.[70,71]

Simocyclinones C and D

Simocyclinones C and D produced by Streptomyces antibioticus Tü 6040, a terrestrical microorganism was isolated in Iguaçu Falls, Argentina.[81,82,83]

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5 thoughts on “SECONDARY METABOLITES WITH CYTOTOXIC AND ANTITUMOR ACTIVITY: PLANTS AND MICROORGANISMS

    1. that’s true.
      There is close relationship between plants as sources of medicines and conservation of plant diversity. If we human being have known how important and safely of traditional medicines from plants, human can improve conservation of plant diversity. I believe we won’t destroy our medicines sources right??

  1. Hello. I´m Martha Gutiérrez
    I´m studing a master degre and I´m interested in the published work of “Secondary metabolite compounds from Jatroph species”.
    I want to know how I can cite. Thank you for your attention.
    Greetings.

    1. Dear Martha
      Article about “Secondary metabolite compounds from Jatropha species” only published in this blog. This is an original article and hasn’t been published in commecial publisher or as scientific journal.
      Thank you.

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