**9.2 Gombamide A**

A cyclothiopeptide consisting of an unusual amino acid residues like pHSA and pyroGlu [72]. It possess moderate inhibitory action towards the, Na+/K+-ATPase.

A specific new class of proline rich cycloheptapeptides derived from the photooxidation of tryptophan consisting of cytotoxic phakellistatin 3 and isophakellistatin 3. This peptides has an unusual amino acid residue such as "Hpi" respectively. These proline rich peptides act in a very divergent way, capable of causing stereospecific interaction with the membrane system. These interactions are caused by the intracellular targeting, compared to the general membrane disruption mode of action of the conventional antimicrobial peptides. It was found that proline rich antimicrobial peptides stereo specifically binds the intracellular foreign particles, such as the bacterial heat shock proteins DnaK. These peptides have a good water solubility, high potential for killing bacteria and lower cytotoxic

#### *Insights on Antimicrobial Peptides*

activity at higher concentrations, these factors contribute to the development of the novel antimicrobial therapeutic agents in the field of medicine [73].

These peptides could easily enter the bacterial cell, binding and disrupting specific targets such as ribosome, thereby inhibiting protein synthesis. However all these factors, concludes that these peptides could subsequently be used as molecular hooks, for identifying intracellular or membrane proteins involved in this mechanism of action [74]. And it could be used for specifically altering novel therapeutics for drug delivery.

Scleritodermin A causes inhibition of tubulin polymerization [75].

Immunosuppressive activity of cyclolinopeptide A results from the formation of complex with cyclophilin and causing inhibition of phosphatase activity of calcineurin, plays an important role in T-lymphocyte signaling [76].

Cemadotin, a water soluble synthetic component of linear peptide dolastatin 15, which is reported to act on microtubules and causing strong suppression of microtubule dynamics [77].

#### **9.3 Didemnin B**

A cyclic depsipeptide derived from the marine cyclopolypeptide undergo clinical trials because of its potential to target oncological patients. Its high toxicity, poor solubility and shorter life span led to the discontinuation of didemnin B in clinical trials [78].

Didemnin B, belonging to a class of heterodetic non-polar cyclic peptide associated with several Antiviral, antitumor, immunomodulating properties, potency inhibits protein and DNA synthesis by binding to eukaryotic translation elongation factor EF-1 in a GTP dependent manner. Formation of the [79] Didemnin B-GTP-EF-1 complex could be responsible for protein synthesis inhibition.

Inhibition of protein synthesis by didemnin B occurs by stabilization of aminoacyl-tRNA to the ribosomal A-site, preventing the translocation of phenylalanyl– tRNA from the A- to the P-site, preventing peptide bond formation.

Tamandarin A acts in a very same mechanism as didemnin B. Aplidine's involves several mechanism of action such as cell cycle arrest and protein synthesis inhibition. It induces early oxidative stress and results in a rapid activation of JNK and p38 MAPK phosphorylation by activating both kinases occurring among before the activation of apoptosis [80].

Didemnin B causes the death of several transformed cells through apoptosis, DNA fragmentation within the cytosol and generation of DNA ladders [81].

A linear depsipeptide kahalalide F, has predominant antifungal and antitumor activity, and underway in clinical trials.

A cyclic depsipeptide Plitidepsin (dehydrodedemnin B or aplidine) is in its clinical trial for being developing it as a drug. In 2003, plitidepsin was given orphan drug status for treating acute lymphoblastic leukemia. In 2007, it underwent phase II clinical trials and in 2006 it is announced for small phase-I clinical trials for treating multiple myeloma [82].

Antimitotic dolastatins group, dolastatin 10 and 15 are undergoing phase-II clinical trials. A synthetic analogue of dolastatin 15, cemadotin is also in phase-II clinical trials for its promising cancer chemotherapeutic agent.

#### **9.4 Ecteinascidian—743**

A specific alkaloid isolated from the tunicate *Ecteinascidia turbinate*, represents a rich source of symbionts whose aqueous extract are known to contain anticancerous agents. Ecteinascidin alkaloids molecular structures are known to be defined as

#### *Antimicrobial Peptides Derived from Ascidians and Associated Cyanobacteria DOI: http://dx.doi.org/10.5772/intechopen.99183*

complex tetrahydroisoquinolones. This alkaloid is a major meatabolite possessing cytotoxic activity against leukemia cells (IC 50 0.5 ng/mL). Ecteinascidins structure is considered to be of a natural microbial origin (eg saframycins) [83]. This alkaloid because of its stability and relatively high natural abundance made it most suitable for entering clinical trials. Ecteinascidians-743, entered phase-I clinical trials after rendering, to have an higher therapeutic index and potency. Recently, it was found that ET-743binds to the minor groove of DNA to induce a bend in the DNA helix towards the major groove. ET-743 plays an important role in causing interference with the cellular transcription coupled nucleotide excision repair to induce cell death and cytotoxicity which is independent of p53 status. However, advanced ovarian, breast and mesenchymal tumors showed more response to ET-743 in phase-I clinical trials. ET-743 in phase-II clinical trials showed more heightened response towards soft tissue sarcoma (STS), ovarian and breast cancer. There are two patents for bacterial symbionts of the tunicate *Ecteinascidia turbinata*, primary focus was on the isolation of the producing microbe, secondary one uses 16S rDNA sequences to identify the endosymbiont as *Endoecteinascidia frumentensis*, the source for producing the ecteinascidins [84].
