Name: Sibiromycin
Brand: BOC Sciences
Rating: 5 (1 reviews)

Synonyms

Sybiromycin; 5H-Pyrrolo(2,1-c)(1,4)benzodiazepin-5-one, 7-((4,6-dideoxy-3-C-methyl-4-(methylamino)-alpha-L-mannopyranosyl)oxy)-1,10,11,11a-treahydro-9,11-dihydroxy-8-methyl-2-(1E)-1-propenyl-, (11R,11aS)-

IUPAC Name

(6R,6aS)-2-[(2S,3R,4R,5S,6S)-3,4-dihydroxy-4,6-dimethyl-5-(methylamino)oxan-2-yl]oxy-4,6-dihydroxy-3-methyl-8-[(E)-prop-1-enyl]-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one

Canonical SMILES

CC=CC1=CN2C(C1)C(NC3=C(C(=C(C=C3C2=O)OC4C(C(C(C(O4)C)NC)(C)O)O)C)O)O

InChI

InChI=1S/C24H33N3O7/c1-6-7-13-8-15-21(30)26-17-14(22(31)27(15)10-13)9-16(11(2)18(17)28)34-23-20(29)24(4,32)19(25-5)12(3)33-23/h6-7,9-10,12,15,19-21,23,25-26,28-30,32H,8H2,1-5H3/b7-6+/t12-,15-,19-,20-,21+,23-,24+/m0/s1

InChIKey

RAGFPHFDFVNLCG-INYQBOQCSA-N

Density

1.41 g/cm3

Solubility

Soluble in methanol, dimethylformamide

Melting Point

>120°C (dec.)

Appearance

Creaminess

Shipping

-20°C (International: -20°C)

Storage

Store at-20°C

Boiling Point

755.7°C at 760 mmHg

In Vitro

Sibiromycin, an antitumour antibiotic forming a stable complex with the double-stranded DNA selectively inhibits the incorporation of [3H]thymidine into the H-strand of mtDNA during the incubation of isolated rat liver mitochondria in vitro.

Sibiromycin is a potent antitumor antibiotic and a promising ADC cytotoxin utilized as an ADC payload in antibody-drug conjugates. Its mechanism involves binding to DNA and inducing strand breaks, leading to apoptosis in rapidly proliferating tumor cells. The high cytotoxicity of Sibiromycin makes it an attractive payload for targeted cancer therapies, especially when incorporated into ADC platforms designed for selective tumor delivery.

Within antibody-drug conjugates, Sibiromycin is conjugated to monoclonal antibodies via cleavable or non-cleavable linker chemistries. This design ensures that the payload remains inactive during systemic circulation and is selectively released inside tumor cells after internalization and enzymatic processing. Such tumor-specific delivery enhances antitumor efficacy while minimizing off-target toxicity, making Sibiromycin a reliable option for precision oncology applications where potent cytotoxic activity is required at low drug-to-antibody ratios (DARs).

Applications of Sibiromycin include its use in preclinical and clinical ADC candidates targeting hematologic malignancies and solid tumors, such as leukemia, lymphoma, breast cancer, and lung cancer. Its chemical structure supports compatibility with diverse linker technologies, optimizing payload stability, conjugation efficiency, and intracellular release. Researchers utilize Sibiromycin to develop next-generation ADCs with enhanced tumor selectivity, improved pharmacokinetics, and potent antitumor activity, enabling innovative and effective targeted cancer therapies.

1. Determination of sibiromycin and its natural derivatives using new analytical and structural approaches

Miriam Chudomelová, Miroslav Sulc, Markéta Jelínková, Iva Fadrhoncová, Jana Olšovská, Jürgen Felsberg J Chromatogr A . 2011 Jan 7;1218(1):83-91. doi: 10.1016/j.chroma.2010.10.110.

A new separation and quantification method using ultra high-performance liquid chromatography (UHPLC) with UV detection was developed for the detection of sibiromycin in fermentation broth of Streptosporangium sibiricum. The solid phase extraction method based on cation-exchange was employed to pre-concentrate and purify fermentation broth containing sibiromycin prior to UHPLC analysis. The whole assay was validated and showed a linear range of detector response for the quantification of sibiromycin in a concentration from 3.9 to 250.0 μg mL⁻¹, with correlation coefficient of 0.999 and recoveries ranging from 71.66±3.55% to 74.76±5.18%. Method limit of quantification of the assay was determined as 0.18 μg mL⁻¹ and was verified with resulting RSD of 9.6% and accuracy of 97.6%. The developed assay was used to determine the sibiromycin production in 12 different fermentation broths. Moreover, several natural sibiromycin analogues/derivatives were described with pilot characterization using off-line mass spectrometry: the previously described dihydro-sibiromycin (DH-sibiromycin) and tentative bis-glycosyl forms of sibiromycin and its dihydro-analogue.

2. Mutasynthesis of a potent anticancer sibiromycin analogue

Isaac T Yonemoto, Natàlia Reixach, Barbara Gerratana, Ankush Khullar, Wei Li ACS Chem Biol . 2012 Jun 15;7(6):973-7. doi: 10.1021/cb200544u.

Pursuit of the actinomycete pyrrolobenzodiazepine natural product sibiromycin as a chemotherapeutic agent has been limited by its cardiotoxicity. Among pyrrolobenzodiazepines, cardiotoxicity is associated with hydroxylation at position 9. Deletion of the methyltransferase gene sibL abolishes the production of sibiromycin. Supplementation of growth media with 4-methylanthranilic acid can substitute for its native 3-hydroxy congener. Cultures grown in this fashion yielded 9-deoxysibiromycin. In this study, we characterize the structure and biological activity of sibiromycin and 9-deoxysibiromycin methyl carbinolamines. Preliminary in vitro evidence suggests that 9-deoxysibiromycin exhibits reduced cardiotoxicity while gaining antitumor activity. These results strongly support further exploration of the production and evaluation of monomeric and dimeric glycosylated pyrrolobenzodiazepine analogues of sibiromycin.

3. A four-enzyme pathway for 3,5-dihydroxy-4-methylanthranilic acid formation and incorporation into the antitumor antibiotic sibiromycin

Femke I Kraas, Mohamed A Marahiel, Tobias W Giessen Biochemistry . 2011 Jun 28;50(25):5680-92. doi: 10.1021/bi2006114.

The antitumor antibiotic sibiromycin belongs to the class of pyrrolo[1,4]benzodiazepines (PBDs) that are produced by a variety of actinomycetes. PBDs are sequence-specific DNA-alkylating agents and possess significant antitumor properties. Among them, sibiromycin, one of two identified glycosylated PBDs, displays the highest DNA binding affinity and the most potent antitumor activity. In this study, we report the elucidation of the precise reaction sequence leading to the formation and activation of the 3,5-dihydroxy-4-methylanthranilic acid building block found in sibiromycin, starting from the known metabolite 3-hydroxykynurenine (3HK). The investigated pathway consists of four enzymes, which were biochemically characterized in vitro. Starting from 3HK, the SAM-dependent methyltransferase SibL converts the substrate to its 4-methyl derivative, followed by hydrolysis through the action of the PLP-dependent kynureninase SibQ, leading to 3-hydroxy-4-methylanthranilic acid (3H4MAA) formation. Subsequently the NRPS didomain SibE activates 3H4MAA and tethers it to its thiolation domain, where it is hydroxylated at the C5 position by the FAD/NADH-dependent hydroxylase SibG yielding the fully substituted anthranilate moiety found in sibiromycin. These insights about sibiromycin biosynthesis and the substrate specificities of the biosynthetic enzymes involved may guide future attempts to engineer the PBD biosynthetic machinery and help in the production of PBD derivatives.

What is Sibiromycin?

Sibiromycin is a naturally derived cytotoxic antibiotic that binds DNA, inhibiting replication and transcription. It is used as a payload in ADCs for targeted cell killing, and its chemical structure allows efficient antibody conjugation.

22/9/2017

Could you kindly advise how Sibiromycin is used in ADCs?

In ADCs, Sibiromycin is attached to antibodies to deliver cytotoxicity selectively to cells expressing specific antigens, reducing off-target toxicity and improving therapeutic index for experimental and preclinical studies.

17/8/2018

Dear team, which linkers are compatible with Sibiromycin ADCs?

Sibiromycin can be conjugated using cleavable linkers for intracellular payload release or non-cleavable linkers for increased systemic stability. Linker selection influences ADC pharmacokinetics and efficacy.

26/2/2020

Could you please advise what handling precautions are necessary for Sibiromycin?

Due to its potent cytotoxicity, Sibiromycin must be handled in controlled laboratory conditions with PPE and containment. Strict adherence to safety protocols is essential during conjugation and experimental handling.

22/12/2018

Good morning! What benefits do Sibiromycin ADCs provide in research?

Sibiromycin ADCs enable targeted cytotoxicity for preclinical evaluation of antibody specificity and payload efficiency. They support research in oncology therapeutics and allow controlled study of ADC pharmacodynamics and pharmacokinetics.

21/2/2018

— Dr. Kevin Wallace, Senior Scientist (USA)

Sibiromycin from BOC Sciences arrived with excellent purity, enabling accurate ADC conjugation.

26/2/2020

— Dr. Matteo Rossi, Molecular Pharmacologist (Italy)

Sibiromycin from BOC Sciences was highly effective for our early-stage drug discovery project. The material quality and reproducibility supported smooth downstream workflows.

21/2/2018

— Dr. Hans Bauer, Medicinal Chemist (Germany)

Fast shipping, thorough QC, and responsive technical support for Sibiromycin.

22/12/2018

— Ms. Caroline Dubois, Molecular Oncology Scientist (France)

Sibiromycin from BOC Sciences met the stringent criteria of our preclinical program. The batch-to-batch uniformity and thorough QC gave us a dependable foundation for downstream research.

22/9/2017

— Dr. Richard Moore, Lead Scientist (USA)

High-purity Sibiromycin and timely delivery enabled efficient pipeline progression.

— Dr. Richard Evans, Drug Discovery Scientist (UK)

Our group evaluated Sibiromycin for novel payload development, and the sample from BOC Sciences was both potent and reproducible. Delivery was punctual, which helped us meet a grant milestone.

17/8/2018