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Not to be confused with Soframycin.
Tetrahydroisoquinoline, overarching family of Saframycin

Saframycins are a group of antitumor antibiotics belonging to the Tetrahydroisoquinoline family.[1] Initially discovered by Arai et al. in 1977, more than 20 species have been discovered over the years.[2]

The family is characterized by their dimeric heterocyclic quinone skeleton.[3] They generally have low solubility in water and n-hexane, moderate solubility in ether and high solubility in lower alcohols, chloroform and acetone.[4] They show varying degrees of antimicrobial properties with a bias of greater effects on gram-positive bacteria, and are generally effective against L1210 leukaemia.[4][5][6][7][8]They also display activities against a variety of diseases such as Ehrlich ascites carcinoma, P388 leukaemia and B16 Melanoma. [4][5][6][7][8]

The Saframycin compounds are currently not clinically prescribed for chemotherapy or otherwise due to their high toxicity, but their derivatives show potential as anti-tumour agents and are going through clinical trials.[9][10][11]

History

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The Saframycin group of compounds were first synthesized by Arai et al in 1977 using Streptomyces lavendulae (a streptothricin-producing strain), with the initial discovery consisting of Saframycin A, Saframycin B, Saframycin C, Saframycin D and Saframycin E.[4] Structures of aforementioned compounds were subsequently published; the structure of Saframycin A was elucidated with 13C NMR spectroscopy at 1979, Saframycin C with X-ray Crystallography and Saframycin B with 13C NMR spectroscopy later in 1979, and Saframycin D with 400MHz NMR spectroscopy in 1987.[12][13][14] Due to Saframycin E’s unstable nature, its structure was proposed by Kubo et al in 1995.[1][15][16]

In the process of optimising production of Saframycin A, a precursor was discovered and isolated in 1981.[3] It was then synthesised by treating Saframycin A with mild acid, which led to hydrolysis and decyanisation, yielding Saframycin S. Initially a hypothesis, the pathway was proven by introducing radioactive nitrile groups (Na14CN) to the culture filtrate where affirmative results were seen through ultraviolet scanning profile and bioautography, thus Saframycin S was concluded to be a precursor of Saframycin A. Its structure was determined through various methods, including spectroscopic tests and chemical reactions.[3]

In 1982, Arai et al. discovered Saframycin AR1(AH2), AR2, AH1 and AR3(BH1) as derivatives of Saframycin A, which was achieved by processing with Rhodococcus amidophilus IFM44.[7] Their structures were also determined through various methods consisting of multiple spectroscopic tests and chemical reactions.[7] AH1 and AH2 could then form AH1Ac and AH2Ac through acetylation.[17]

Another variant, Saframycin R, was reported by Arai et al. in 1982 while investigating minor components in the Streptomyces lavendulae No.314 culture.[8] 4 structures were proposed by Arai et al. in 1982 based on its spectroscopic and chemical data, and was confirmed by Kubo et al. in 2000 by running heteronuclear correlation experiments (HMQC and HMBC) on its acylated compounds.[9]

Variants Saframycin F, G and H were isolated in 1984, and their structures were determined through various spectroscopic methods in 1988.[17][18]

In 1985, Arai et al. attempted to alter the side chains of Saframycin A, which resulted in the generation of the new Saframycins Yd-1, Yd-2 and Y3, which had 2-amino-n-butyric acid, glycine, and alanine residues respectively substituting the pyruvic acid normally located in the N-terminal side chain of Saframycin A.[19] In subsequent publications, similar methods with different reagents yielded the new compounds Ad-1, Y2b-d and Y2b, and structures of all aforementioned compounds were elucidated with various spectroscopic methods.

Mx1 and Mx2 were discovered by Kienast et al. in the culture broth of Myxococcus xanthus (strain Mx x48) in 1988.[20][21][22] The isolated compounds were named Mx1 and Mx2, and the structures were elucidated through various spectroscopic methods.[20][21][22]

Types of Saframycin

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Saframycin A

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Properties

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Saframycin A is a yellow powder under standard conditions with chemical structure C29H30N4O8.[3] Aside from the Saframycin group’s dimeric heterocyclic quinone skeleton, Saframycin A is characterised by its nitrile group at C-21, which facilitates interaction with DNA.[3]

Saframycin A displays high levels of activity against P388 leukaemia and Ehrlich ascites carcinoma, and displayed moderate activity against B16 melanoma and L1210 leukaemia.[5] In vivo tests on Ehrlich ascites carcinoma also demonstrated its secondary prophylactic effects indicated by subjects developing resistance after being cured by Saframycin A.[5]

Production

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The bacteria strain Streptomyces lavendulae is used to produce Saframycin A.[4] The extraction of such is similar to the extraction of Chlorocarcins with the same culture broth, with the omission of sodium hydroxide (NaOH) counter extraction, therefore yielding Saframycin instead of Chlorocarcins.[23]

The bacteria is first cultured on a glucose-asparagine agar slant and then fermented to create an inoculum, which is then used to seed the production medium for antibiotic production during the subsequent fermentation.[4]

As multiple antibiotics are produced by the bacteria, Saframycin A has to be isolated from the culture.[4] The culture is filtered and concentrated with a thin-film evaporator to a concentrate, which is then extracted with multiple solvents.[4] Stearic acid is isolated from the aqueous layer, while the ethyl acetate layer undergoes repeated extractions with HCl, which is then adjusted to pH 10 and extracted with chloroform.[23] The chloroform extract is vacuum dried to yield basic components, while the ethyl acetate layer undergoes counter extraction with n-hexane and aqueous methanol, which is then washed with HCl (with the aforementioned omission of NaOH counter extraction).[23] Further extraction, concentration and purification yields Saframycin.[4]

Subsequent investigations revealed that adding Sodium Cyanide (NaCN) to the culture broth induces an increased Saframycin A potency; incorporation of metabolic end products phenylalanine and tryptophan also stimulates Saframycin A production; preventing bacterial degradation by maintaining the culture's pH below 5.5 also contributes to an increase in output. The combination of the aforementioned methods results in a 1000-fold increase in production yield compared to the original method.[3]

Mechanism

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DNA Alkylating iminium ion

Saframycin A possesses a nitrile group (leaving group) at C-21, and when reduced to its hydroquinone form, the leaving group can be ejected and a DNA alkylating iminium ion can be formed, which subsequently binds to and alkylates DNA.[24][25] When binding to DNA, Saframycin A shows specificity to strands 5’-GGG or 5’-GGC, and binds selectively to the minor groove.[26]

Saframycin A is also capable of forming adducts with GAPDH, which can induce toxic responses in cells, causing antiproliferative effects.[27]

Derivatives

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Saframycin AR1, AR2 and AR3 - AR group of derivatives, later found to be AH

Saframycin AR1, AR2 and AR3 are derivatives of Saframycin A, with chemical compositions of 25-dihydroSaframycin A, Saframycin B and  21-decyano-25-dihydroSaframycin A respectively.[7][28] Initially synthesized through conversion with Rhodococcus amidophilus IFM 144, it was later discovered that conversion could also be carried out by various actinomycetes, yielding different combination of compounds; the Mycobacterium type only produces Saframycin AR1, Nocardia type produces ARI, AR2 and AR3 and Streptomyces is unable to produce derivatives.[7][28]

Saframycins A, AR1 and AR3 had ED50 values of  0.003 ug/ml, 0.004 ug/ ml, and 0.35 ug/ml, respectively, against L1210 mouse leukaemia cell lines.[7][28] In vivo studies with AR1 showed an increased lifespan of mice with L1210 mouse leukaemia, with similar efficacy to Saframycin A; AR3, on the other hand, did not exhibit antitumor activities.[7][28] Saframycin AR1 was also shown to have one-tenth of Saframycin A’s antimicrobial activity (with a bias towards gram-positive bacteria), with AR3 being another 10 to 50 folds less active.[7][28]

Saframycin AH1 and AH2

Saframycin AH1 and AH2 were synthesised through chemical reduction of Saframycin A with NaBH4, yielding the aforementioned derivatives in a 1:1 ratio.[7] AH1 and AH2 are stereoisomers at C-25, with AH2 being structurally identical to AR1.[7]

Saframycin BH1 and BH2

Saframycin BH1 and BH2 were synthesised through chemical reduction of Saframycin B with NaBH4, yielding a 10:1 ratio of BH1 to BH2. BH1 is structurally identical to AR3, and BH1 and BH2 were assumed to be stereoisomers.[7]

Name Chemical name Alternative name (synonymous with)
AR family AH family BH family Stereoisomer of
AR1 25-dihydroSaframycin A AH2
AR2 Saframycin B
AR3 21-decyano-25-dihydroSaframycin A BH1
AH1 AH2
AH2 AR1 AH1
BH1 AR3 (BH2)
BH2 (BH1)

Saframycin S

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Properties

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Saframycin S is a dark yellow powder under standard conditions with chemical structure C2H31N3O9.[3] It is a precursor to Saframycin A with the chemical structure of decyano-Saframycin A, originally discovered through an attempt to increase production yield of Saframycin A by introducing Sodium Cyanide (NaCN) to the culture filtrate of Streptomyces lavendulae No. 314.[3] Cyanation of Saframycin S yields Saframycin A; while the reverse can be done by mild acid hydrolysis, decyanation of Saframycin A and yielding Saframycin S.[3]

Saframycin S shows the highest gram-positive antimicrobial properties (around 3-4 times of Saframycin A) among the Saframycin family. It is also active against Ehrlich ascites tumor and displays moderate activity against L1210 leukaemia and P388 leukaemia.[6]

Mechanism

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SaframycinS exists in 2 interconvertible forms - iminium salt and α-carbinolamine, the latter of which possesses an α-carbinolamine group (containing a leaving group) at C-21 which is identified to be responsible for its potent cytotoxic properties.[6][17]

Saframycin S, like all Saframycins, recognizes and alkylates specific sequences (general sequences recognized by Saframycins 5’-GGG and 5’CCC; Saframycin S specific sequences 5’CGG and 5’CTA) in the DNA minor groove.[25][26] In its iminium cation form, Saframycin S is capable of attacking amino groups of guanine, which results in the formation of an Aminal linkage.[25][26]

Saframycin S capable of another covalent bonding mechanism; this pathway necessitates the reduction of Saframycin S to dihydroquinone, which subsequently encourages the formation of an alkylating iminium species.[25][26]

Related compounds and clinical uses

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Among the plethora of Saframycins, Saframycin A is one of the most well researched compounds among the Saframycin family.[8] Although highly potent and promising, its high toxicity is a major hindrance to its development as a chemotherapeutic drug; yet similar compounds show high potential as anti-tumour drugs among other purposes, and are currently undergoing clinical development.[8]

Zalypsis

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Zalypsis is a synthetic alkaloid which is structurally related to the Saframycin family, and like Saframycins, also functions as a DNA alkylating agent.[29] The compound is currently undergoing late phase 1 drug trials with the target of solid tumours and shows an acceptable toxicity profile along with high potency.[29]

Ecteinascidin 743

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Ecteinascidin 743 is a marine natural product derived antitumor drug that has been approved by the European Commission and the U.S. FDA, and is currently being prescribed to treat soft tissue sarcomas.[30] Owing to the presence of a C ring, Ecteinascidin 743 has a higher antitumor activity than the structurally related Saframycin A.[31]

As 1 tonne of Ecteinascidia turbinata is required to form 1 gram of the drug, great interest was shown in the total synthesis of the compound, with the first success in 1996 and subsequent publications of different methods in the following years.[30]

Reference list

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  1. ^ a b Scott, Jack D.; Williams, Robert M. (2002-05-01). "Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibiotics". Chemical Reviews. 102 (5): 1669–1730. doi:10.1021/cr010212u. ISSN 0009-2665.
  2. ^ Ozturk, Turan (1999), "Alkaloids Containing an Isoquinolinequinone Unit", The Alkaloids: Chemistry and Biology, vol. 53, Elsevier, pp. 119–238, doi:10.1016/s1099-4831(08)60061-9, ISBN 978-0-12-469553-5, retrieved 2024-04-10
  3. ^ a b c d e f g h i Arai, Tadashi; Takahashi, Katsuhiro; Ishiguro, Kimiko; Yazawa, Katsukiyo (1980). "Increased production of saframycin A and isolation of saframycin S." The Journal of Antibiotics. 33 (9): 951–960. doi:10.7164/antibiotics.33.951. ISSN 0021-8820.
  4. ^ a b c d e f g h i Takahashi, Katsuhiro; Kubo, Akinori (1977). "New antibiotics, saframycins A, B, C, D and E." The Journal of Antibiotics. 30 (11): 1015–1018. doi:10.7164/antibiotics.30.1015. ISSN 0021-8820.
  5. ^ a b c d Arai, Tadashi; Takahashi, Katsuhiro; Ishiguro, Kimiko; Mikami, Yuzuru (1980). "Some Chemotherapeutic Properties of Two New Antitumor Antibiotics, Saframycins a and C". GANN Japanese Journal of Cancer Research. 71 (6): 790–796. doi:10.20772/cancersci1959.71.6_790.
  6. ^ a b c d Mikami, Yuzuru; Yokoyama, Koji; Tabeta, Hiroshi; Nakagaki, Kazuhide; Arai, Tadashi (1981). "Saframycin S, a new saframycin group antibiotic". Journal of Pharmacobio-Dynamics. 4 (4): 282–286. doi:10.1248/bpb1978.4.282. ISSN 0386-846X.
  7. ^ a b c d e f g h i j k l Takahashi, Katsuhiro; Yazawa, Katsukiyo; Kishi, Koichiro; Mikami, Yuzuru; Arai, Tadashi; Kubo, Akinori (1982). "Microbial conversion of saframycin A to 25-dihydrosaframycin A and 21-decyano-25-dihydrosaframycin A (25-dihydrosaframycin B) and their biological activities". The Journal of Antibiotics. 35 (2): 196–202. doi:10.7164/antibiotics.35.196. ISSN 0021-8820.
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  9. ^ a b Saito, Naoki; Kameyama, Noriko; Kubo, Akinori (2000-12-15). "Structure of Saframycin R". Tetrahedron. 56 (51): 9937–9944. doi:10.1016/S0040-4020(00)00972-8. ISSN 0040-4020.
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  11. ^ Erba, E; Bergamaschi, D; Bassano, L; Damia, G; Ronzoni, S; Faircloth, G.T; D'Incalci, M (2001). "Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action". European Journal of Cancer. 37 (1): 97–105. doi:10.1016/S0959-8049(00)00357-9.
  12. ^ Arai, T.; Takahashi, K.; Nakahara, S.; Kubo, A. (1980-09-01). "The structure of a novel antitumor antibiotic, saframycin A". Experientia. 36 (9): 1025–1027. doi:10.1007/BF01965946. ISSN 0014-4754.
  13. ^ Arai, Tadashi; Takahashi, Katsuhiro; Kubo, Akinori; Nakahara, Shinsuke; Sato, Sadao; Aiba, Kimie; Tamura, Chihiro (1979-01-01). "The structures of novel antibiotics, saframycin B and C". Tetrahedron Letters. 20 (25): 2355–2358. doi:10.1016/S0040-4039(01)93972-3. ISSN 0040-4039.
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  15. ^ Saito, Naoki; Harada, Shunji; Nishida, Masayo; Inouye, Izumi; Kubo, Akinori (1995). "Synthesis of Saframycins. X. Transformation of (-)-Saframycin A to (-)-Saframycin Mx Type Compound with the Structure Proposed for Saframycin E". Chemical & Pharmaceutical Bulletin. 43 (5): 777–782. doi:10.1248/cpb.43.777.
  16. ^ Ozturk, Turan (1999), "Alkaloids Containing an Isoquinolinequinone Unit", The Alkaloids: Chemistry and Biology, vol. 53, Elsevier, pp. 119–238, doi:10.1016/s1099-4831(08)60061-9, ISBN 978-0-12-469553-5, retrieved 2024-04-10
  17. ^ a b c Kishi, Koichiro; Yazawa, Katsukiyo; Takahashi, Katsuhiro; Mikami, Yuzuru; Arai, Tadashi (1984). "STRUCTURE-ACTIVITY RELATIONSHIPS OF SAFRAMYCINS". The Journal of Antibiotics. 37 (8): 847–852. doi:10.7164/antibiotics.37.847. ISSN 0021-8820.
  18. ^ Mikami, Yuzuru; Takahashi, Katsuhiro; Yazawa, Katsukiyo; Hour-Young, Chen; Arai, Tadashi; Saito, Naoki; Kubo, Akinori (1988-06-25). "STRUCTURAL STUDIES ON MINOR COMPONENTS OF SAFRAMYCIN GROUP ANTIBIOTICS SAFRAMYCINS F, G AND H". The Journal of Antibiotics. 41 (6): 734–740. doi:10.7164/antibiotics.41.734. ISSN 0021-8820.
  19. ^ Arai, T; Yazawa, K; Takahashi, K; Maeda, A; Mikami, Y (1985). "Directed biosynthesis of new saframycin derivatives with resting cells of Streptomyces lavendulae". Antimicrobial Agents and Chemotherapy. 28 (1): 5–11. doi:10.1128/AAC.28.1.5. ISSN 0066-4804.
  20. ^ a b Ozturk, Turan (1999), "Alkaloids Containing an Isoquinolinequinone Unit", The Alkaloids: Chemistry and Biology, vol. 53, Elsevier, pp. 119–238, doi:10.1016/s1099-4831(08)60061-9, ISBN 978-0-12-469553-5, retrieved 2024-04-10
  21. ^ a b Trowitzsch‐Kienast, Wolfram; Irschik, Herbert; Reichenbach, Hans; Wray, Victor; Höfle, Gerhard (1988-05-13). "Antibiotika aus Gleitenden Bakterien, XXXV. Isolierung und Strukturaufklärung der Saframycine Mx 1 und Mx 2, neue antitumor‐aktive Antibiotika aus Myxococcus xanthus". Liebigs Annalen der Chemie. 1988 (5): 475–481. doi:10.1002/jlac.198819880518. ISSN 0170-2041.
  22. ^ a b Irschik, Herbert; Trowitzsch-Kienast, Wolfram; Gerth, Klaus; Hofle, Gerhard; Reichenbach, Hans (1988). "Saframycin Mx1, a new natural saframycin isolated from a myxobacterium". The Journal of Antibiotics. 41 (8): 993–998. doi:10.7164/antibiotics.41.993. ISSN 0021-8820.
  23. ^ a b c Arai, Tadashi; Yazawa, Katsukiyo; Mikami, Yuzuru; Kubo, Akinori; Takahashi, Katsuhiro (1976). "ISOLATION AND CHARACTERIZATION OF SATELLITE ANTIBIOTICS, MIMOSAMYCIN AND CHLOROCARCINS FROM STREPTOMYCES LAVENDULAE, STREPTOTHRICIN SOURCE". The Journal of Antibiotics. 29 (4): 398–407. doi:10.7164/antibiotics.29.398. ISSN 0021-8820.
  24. ^ Gates, Kent S. (1999), "Covalent Modification of DNA by Natural Products", Comprehensive Natural Products Chemistry, Elsevier, pp. 491–552, doi:10.1016/b978-0-08-091283-7.00074-6, ISBN 978-0-08-091283-7, retrieved 2024-04-10
  25. ^ a b c d Avendaño, Carmen; Menéndez, J. Carlos (2008), "Alkylating and Non-Alkylating Compounds Interacting with the DNA Minor Groove", Medicinal Chemistry of Anticancer Drugs, Elsevier, pp. 177–198, doi:10.1016/b978-0-444-52824-7.00006-8, ISBN 978-0-444-52824-7, retrieved 2024-04-10
  26. ^ a b c d Rao, K. Ekambareswara; Lown, J. William (1990). "Mode of action of saframycin antitumor antibiotics: sequence selectivities in the covalent binding of saframycins A and S to deoxyribonucleic acid". Chemical Research in Toxicology. 3 (3): 262–267. doi:10.1021/tx00015a012. ISSN 0893-228X.
  27. ^ Xing, Chengguo; LaPorte, Jacob R.; Barbay, Joseph K.; Myers, Andrew G. (2004-04-20). "Identification of GAPDH as a protein target of the saframycin antiproliferative agents". Proceedings of the National Academy of Sciences. 101 (16): 5862–5866. doi:10.1073/pnas.0307476101. ISSN 0027-8424. PMC 395888. PMID 15079082.{{cite journal}}: CS1 maint: PMC format (link)
  28. ^ a b c d e Yazawa, Katsukiyo; Asaoka, Takemitsu; Takahashi, Katsuhiro; Mikami, Yuzuru; Arai, Tadashi (1982). "Bioconversions of Saframycin A specific to some genera of Actinomycetes". The Journal of Antibiotics. 35 (7): 915–917. doi:10.7164/antibiotics.35.915. ISSN 0021-8820.
  29. ^ a b Ocio, Enrique M.; Maiso, Patricia; Chen, Xi; Garayoa, Mercedes; Álvarez-Fernández, Stela; San-Segundo, Laura; Vilanova, David; López-Corral, Lucía; Montero, Juan C.; Hernández-Iglesias, Teresa; de Álava, Enrique; Galmarini, Carlos; Avilés, Pablo; Cuevas, Carmen; San-Miguel, Jesús F. (2009-04-16). "Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks". Blood. 113 (16): 3781–3791. doi:10.1182/blood-2008-09-177774. ISSN 0006-4971.
  30. ^ a b Wang, Yue; Jia, Junhao; Zhou, Qin; Chen, Ruijiao; Chen, Xiaochuan (2023-10-12). "Asymmetric synthesis of phthalascidin, zalypsis and renieramycin T from N-Cbz-L-tyrosine". Tetrahedron. 146: 133624. doi:10.1016/j.tet.2023.133624. ISSN 0040-4020.
  31. ^ Guirouilh-Barbat, Josée; Antony, Smitha; Pommier, Yves (2009-07-01). "Zalypsis (PM00104) is a potent inducer of γ-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition". Molecular Cancer Therapeutics. 8 (7): 2007–2014. doi:10.1158/1535-7163.MCT-09-0336. ISSN 1535-7163. PMC 7282704. PMID 19584237.{{cite journal}}: CS1 maint: PMC format (link)
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